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Zhang L, Xiao K, Zhang S, Zhao S, Liu Z, Wang M, Qin K, Yu Y, Li S, Ma L, Sun J. SOCS2 inhibits the tumorigenesis of GISTs and increases the sensitivity of GISTs to imatinib by suppression of KIT activation. Sci Rep 2025; 15:4779. [PMID: 39922931 PMCID: PMC11807132 DOI: 10.1038/s41598-025-89477-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 02/05/2025] [Indexed: 02/10/2025] Open
Abstract
The suppressors of cytokine signaling 2 (SOCS2) inhibits growth hormone receptor (GHR) signaling by negative feedback in the regulation of metabolism. In this study, we found that GHR upregulates SOCS2 expression, whereas KIT mutations, the key driver mutations of gastrointestinal stromal tumors (GISTs), inhibits SOCS2 expression in GISTs. Furthermore, SOCS2 associated and inhibited the activation of KIT mutations, but not wild-type KIT, in addition to its inhibition of GHR signaling, suggesting that KIT mutations may promote their activation by downregulation of SOCS2 expression. Accordingly, SOCS2 inhibited GIST cell survival and proliferation in vitro. In KITV558A/WT mice, knockout of SOCS2 expression increased the tumorigenesis of GISTs and decreased the life span of the mice. In addition, the presence of SOCS2 increased the inhibition of KIT signaling and GIST cell survival and proliferation by imatinib in vitro, and imatinib treatment further reduced tumor growth in KITV558A/WT mice compared with that in KITV558A/WT/SOCS2-/- mice, indicating the key role of SOCS2 in the sensitivity of GISTs to the targeted therapy. Taken together, our data revealed the key role of SOCS2 in the tumorigenesis of GISTs and the sensitivity of GISTs to the targeted therapy, providing a better basis for the improved treatment strategy.
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Affiliation(s)
- Liangying Zhang
- School of Basic Medical Sciences, Ningxia Medical University, Shengli Street 1160, Yinchuan, 750004, China
| | - Kun Xiao
- School of Basic Medical Sciences, Ningxia Medical University, Shengli Street 1160, Yinchuan, 750004, China
| | - Shaoting Zhang
- School of Basic Medical Sciences, Ningxia Medical University, Shengli Street 1160, Yinchuan, 750004, China
| | - Sien Zhao
- School of Basic Medical Sciences, Ningxia Medical University, Shengli Street 1160, Yinchuan, 750004, China
| | - Zimei Liu
- Department of Oncology, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Xianxia Road 1111, Shanghai, 200336, China
| | - Ming Wang
- School of Basic Medical Sciences, Ningxia Medical University, Shengli Street 1160, Yinchuan, 750004, China
| | - Kaiyue Qin
- School of Basic Medical Sciences, Ningxia Medical University, Shengli Street 1160, Yinchuan, 750004, China
| | - Yuanyuan Yu
- The General Hospital of Ningxia Medical University, Yinchuan, China
| | - Shujing Li
- The General Hospital of Ningxia Medical University, Yinchuan, China
| | - Lijun Ma
- Department of Oncology, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Xianxia Road 1111, Shanghai, 200336, China.
| | - Jianmin Sun
- School of Basic Medical Sciences, Ningxia Medical University, Shengli Street 1160, Yinchuan, 750004, China.
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Zhang P, Pei B, Yi C, Akanyibah FA, Mao F. The role of suppressor of cytokine signaling 3 in inflammatory bowel disease and its associated colorectal cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167578. [PMID: 39571630 DOI: 10.1016/j.bbadis.2024.167578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024]
Abstract
Inflammatory bowel disease (IBD) and colorectal cancer (CRC), as two of the major human intestinal diseases, provide challenges for the medical field. Suppressor of cytokine signaling 3 (SOCS3), a protein molecule that negatively regulates cytokine signaling through multiple pathways, is involved in the regulation of various inflammatory diseases and tumors. In IBD, SOCS3 acts on a variety of cells to repair mucosal damage and balance the immune response, including epithelial cells, macrophages, dendritic cells, neutrophils, and T cells. In CRC, SOCS3 is inextricably linked to tumor cell proliferation, invasion, metastasis, and drug resistance. Therefore, it is crucial to systematically investigate the pathogenic involvement of SOCS3 in IBD and CRC. This article reviews the mechanisms and pathways by which SOCS3 is involved in the inhibition of IBD and the mitigation of CRC, and details the therapeutic options for targeting SOCS3.
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Affiliation(s)
- Pengfei Zhang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China; Institute of Hematology, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian 223800, Jiangsu, PR China
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang College, Zhenjiang 212028, PR China
| | - Francis Atim Akanyibah
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China
| | - Fei Mao
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China; Institute of Hematology, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China.
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Mahdi AK, Fitzpatrick DS, Hagen DE, McNabb BR, Urbano Beach T, Muir WM, Werry N, Van Eenennaam AL, Medrano JF, Ross PJ. Efficient Generation of SOCS2 Knock-Out Sheep by Electroporation of CRISPR-Cas9 Ribonucleoprotein Complex with Dual-sgRNAs. CRISPR J 2025; 8:13-25. [PMID: 39807995 DOI: 10.1089/crispr.2024.0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025] Open
Abstract
In mice, naturally occurring and induced mutations in the suppressor of cytokine signaling-2 (Socs2) gene are associated with a high growth phenotype characterized by rapid post-weaning weight gain and 30-50% heavier mature body weight. In this work, we demonstrate an electroporation-based method of producing SOCS2 knock-out (KO) sheep. Electroporation of dual-guide CRISPR-Cas9 ribonucleoprotein complexes targeting SOCS2 was performed 6 h post-fertilization in sheep zygotes. Fifty-two blastocysts were transferred to 13 estrus-synchronized recipients, yielding five live lambs and one stillborn. These lambs all carried mutations predicted to result in SOCS2 KO. Three carried large deletion alleles which evaded detection in initial PCR screening. Off-target analysis using whole genome sequencing comparing the frequency of mutations in regions within 100 bp of possible sgRNA binding sites (up to 4 bp mismatches) and elsewhere in the genome showed no significant difference when comparing unedited control sheep to edited animals (p = 0.71). In conclusion, electroporation of zygotes with dual-guide CRISPR-Cas9 RNPs was effective at generating knock-out sheep with no substantial off-target activity.
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Affiliation(s)
- Ahmed K Mahdi
- Department of Animal Science, University of California, Davis, California, USA
| | - Devon S Fitzpatrick
- Department of Animal Science, University of California, Davis, California, USA
| | - Darren E Hagen
- Department of Animal Sciences, Oklahoma State University, Stillwater, Oklahoma, USA
| | - Bret R McNabb
- School of Veterinary Medicine, University of California, Davis, California, USA
| | - Tara Urbano Beach
- School of Veterinary Medicine, University of California, Davis, California, USA
| | - William M Muir
- Department of Animal Sciences, Purdue University, Lafayette, Indiana, USA
| | - Nicholas Werry
- Department of Animal Science, University of California, Davis, California, USA
| | | | - Juan F Medrano
- Department of Animal Science, University of California, Davis, California, USA
| | - Pablo J Ross
- Department of Animal Science, University of California, Davis, California, USA
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Jia J, Zhou X, Chu Q. Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer. Mol Cell Biochem 2025; 480:1-17. [PMID: 38519710 DOI: 10.1007/s11010-024-04983-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/29/2024] [Indexed: 03/25/2024]
Abstract
Liver cancer (LC) poses a significant global health challenge due to its high incidence and poor prognosis. Current systemic treatment options, such as surgery, chemotherapy, radiofrequency ablation, and immunotherapy, have shown limited effectiveness for advanced LC patients. Moreover, owing to the heterogeneous nature of LC, it is crucial to uncover more in-depth pathogenic mechanisms and develop effective treatments to address the limitations of the existing therapeutic modalities. Increasing evidence has revealed the crucial role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in the pathogenesis of LC. The specific mechanisms driving the JAK-STAT pathway activation in LC, participate in a variety of malignant biological processes, including cell differentiation, evasion, anti-apoptosis, immune escape, and treatment resistance. Both preclinical and clinical investigations on the JAK-STAT pathway inhibitors have exhibited potential in LC treatment, thereby opening up avenues for the development of more targeted therapeutic strategies for LC. In this study, we provide an overview of the JAK-STAT pathway, delving into the composition, activation, and dynamic interplay within the pathway. Additionally, we focus on the molecular mechanisms driving the aberrant activation of the JAK-STAT pathway in LC. Furthermore, we summarize the latest advancements in targeting the JAK-STAT pathway for LC treatment. The insights presented in this review aim to underscore the necessity of research into the JAK-STAT signaling pathway as a promising avenue for LC therapy.
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Affiliation(s)
- JunJun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang, China.
| | - Xuelian Zhou
- Division of Endocrinology, National Clinical Research Center for Child Health, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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Herrera-Uribe J, Convery O, ALmohammadi D, Weinberg FI, Stevenson NJ. The Neglected Suppressor of Cytokine Signalling (SOCS): SOCS4-7. Inflammation 2024:10.1007/s10753-024-02163-7. [PMID: 39460806 DOI: 10.1007/s10753-024-02163-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/30/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024]
Abstract
SOCS proteins are essential for the regulation of oncogenic, anti-pathogenic, and proinflammatory signalling cascades, including the JAK/STAT and NF-kB pathways, where they act as negative feedback regulators. Given their powerful role in a broad spectrum of biological processes, it is surprising that the functions of many SOCS proteins have not been widely explored. While the mechanisms of action of CIS, SOCS1-3 are well-documented, information regarding SOCS4-7 remains limited. However, recent studies have begun to elucidate the regulatory functions of these proteins during infection and disease, such as influenza infection, cancer and diabetes. Therefore, this review aims to describe and discuss studies detailing our current understanding of SOCS4-7, painting a clearer picture of the biological processes these regulatory proteins maintain. Indeed, our review highlights important evidence proving that all SOCS play a role in biological processes that are essential for normal immunological homeostasis, clearance of infection and avoidance of disease. Understanding how SOCS proteins interact with other proteins or how they are dysregulated in disease is likely to provide valuable insights for advancing therapeutic approaches.
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Affiliation(s)
- Juber Herrera-Uribe
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Orla Convery
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Daniah ALmohammadi
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Fabienne Ingrid Weinberg
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Nigel J Stevenson
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
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Yuan M, Shi H, Wang B, Cai J, Yu W, Wang W, Qian Q, Wang Y, Zhou X, Liu J. Targeting SOCS2 alleviates myocardial fibrosis by reducing nuclear translocation of β-catenin. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119804. [PMID: 39084528 DOI: 10.1016/j.bbamcr.2024.119804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/25/2024] [Accepted: 07/20/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Myocardial fibrosis is an important pathological feature of dilated cardiomyopathy (DCM). The roles of SOCS2 in fibrosis of different organs are controversial. Herein, we investigated the function and potential mechanism of SOCS2 in myocardial fibrosis. METHODS Bioinformatics, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), real-time fluorescence quantitative PCR (qPCR), rat primary myocardial fibroblasts (rCFs) culture, doxorubicin (DOX) induced mouse dilated cardiomyopathy (DCM) model, and in vivo adeno-associated virus (AAV) infection were used to explore the role of SOCS2 in DCM. RESULTS Bioinformatics analysis showed that SOCS2 was positively correlated with fibrosis related factors. SOCS2 was significantly upregulated in patients and mice with DCM. In vivo experiments showed that targeted inhibition of cardiac SOCS2 could improve mouse cardiac function and alleviate myocardial fibrosis. Further research demonstrated that SOCS2 promoted the transformation of myofibroblasts. Knockdown of SOCS2 reduced the nuclear localization of β-catenin, which inhibited the fibrogenic effect of Wnt/β-catenin pathway. In addition, bioinformatics analysis suggested that lymphoid enhancer binding factor 1 (LEF1) was significantly positively correlated with SOCS2. Finally, dual luciferase assays demonstrated that LEF1 could bind to the promoter region of SOCS2, thereby mediating its transcriptional activation. CONCLUSION SOCS2 could activate the Wnt/β-catenin by regulating the nuclear translocation of β-catenin, which induces the transcriptional activation of SOCS2. Overall, these results indicated a positive feedback activation phenomenon between SOCS2, β-catenin and LEF1 in DCM. These results suggested that inhibition of SOCS2 could effectively alleviate the progression of myocardial fibrosis and improve cardiac function.
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Affiliation(s)
- Ming Yuan
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China
| | - Hongjie Shi
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China
| | - Bin Wang
- Department of Cardiovascular Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Jie Cai
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China
| | - Wenjun Yu
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China
| | - Wei Wang
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China
| | - Qiaofeng Qian
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China
| | - Yumou Wang
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China
| | - Xianwu Zhou
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China.
| | - Jinping Liu
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan 430071, China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan 430071, China.
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Cui X, Wu C, Xu Y, Zou C, Jiang X. Therapeutic effect and mechanism of Ento-PB on ulcerative colitis in BALB/c mice induced by sodium dextran sulfate. Heliyon 2024; 10:e34539. [PMID: 39149063 PMCID: PMC11325667 DOI: 10.1016/j.heliyon.2024.e34539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/06/2024] [Accepted: 07/11/2024] [Indexed: 08/17/2024] Open
Abstract
The traditional Chinese medicine (TCM) formula Ento-PB containing Periplaneta americana (Linnaeus) (Blattidae) and Taraxacum mongolicum Hand.-Mazz. (Compositae) has great potential for treating inflammation. Thus, this study aimed to explore the pharmacodynamic effect of Ento-PB on DSS-induced ulcerative colitis in BALB/c mice, and its effects on immune function, JAK2/STAT3-related signaling pathways and intestinal flora in UC mice. It was identified that the extract Ento-PB mainly contained 20 compounds, accounting for 78.50 % of the total peak area. Compared with the model group, each dose group of Ento-PB could reduce the DAI score, colon index, CMDI score and colon HS score of mice to varying degrees (P < 0.05 or P < 0.01). Ento-PB can reduce the content of IL-1β, TNF-α, IFN-γ in serum and IL-7 and IL-17 in colonic tissue, and increase IL-2, IL-10 in serum and EGF in colonic mucosa, TGF-β1 expression level (P < 0.05 or P < 0.01). In conclusion, Ento-PB has a good therapeutic effect on DSS-induced UC mice. Its mechanism of action may be to up-regulate the levels of IL-2, IL-10, EGF, IL-22 and TGF-β1, and down-regulate the levels of TNF-α,IFN-γ, IL-7 and IL-17 in UC mice. This provides sufficient experimental basis for the clinical treatment of UC with Ento-PB.
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Affiliation(s)
- Xueping Cui
- Department of Pharmacy, Lishui People's Hospital, Lishui, 323000, China
| | - Chunmei Wu
- Department of Pharmacy, Lishui Second People's Hospital, Lishui, 323000, China
| | - Yusheng Xu
- College of Agronomy, Hunan Agricultural University, Changsha, 410128, China
| | - Chunchu Zou
- Department of Pharmacy, Lishui People's Hospital, Lishui, 323000, China
| | - Xiayun Jiang
- Department of Pharmacy, Lishui People's Hospital, Lishui, 323000, China
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Morelli M, Madonna S, Albanesi C. SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation. Front Immunol 2024; 15:1393799. [PMID: 38975347 PMCID: PMC11224294 DOI: 10.3389/fimmu.2024.1393799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 06/07/2024] [Indexed: 07/09/2024] Open
Abstract
SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.
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Affiliation(s)
| | - Stefania Madonna
- Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata - Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
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Saito M, Nishi H, Takahashi SI, Hakuno F, Miyata I. Growth hormone resistance induced by amino acid deprivation in fao cells is independent of FGF21. Biochem Biophys Res Commun 2024; 709:149811. [PMID: 38569244 DOI: 10.1016/j.bbrc.2024.149811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 04/05/2024]
Abstract
Adequate dietary intake of amino acids is imperative for normal animal growth. Our previous work using rat hepatocarcinoma Fao cells demonstrated that growth hormone (GH) resistance, coupled with a concurrent reduction in insulin-like growth factor 1 (Igf1) mRNA levels, may underlie the growth retardation associated with a low-protein diet (LPD). In this study, we investigated whether FGF21 contributes to liver GH resistance in Fao rat hepatoma cells under amino acid deprivation conditions. Mice subjected to an LPD exhibited growth retardation, compromised GH signaling in the liver, and decreased blood IGF-1 levels compared with those on a control diet. To assess the potential involvement of fibroblast growth factor (FGF) 21, produced in response to amino acid deficiency, in the development of GH resistance, we examined GH signaling and Igf1 mRNA levels in Fao cells cultured in amino acid-deprived medium. Despite the inhibition of Fgf21 expression by the integrated stress response inhibitor, an inhibitor of the eukaryotic initiation factor 2-activating transcription factor 4 pathway, GH resistance persisted in response to amino acid deprivation. Additionally, the introduction of FGF21 into the control medium did not impair either GH signaling or GH-induced Igf1 transcription. These data suggest that, in Fao cells, amino acid deprivation induces GH resistance independently of FGF21 activity. By shedding light on the mechanisms behind growth retardation-associated GH resistance linked to amino acid deficiencies, our findings provide valuable insights for clinicians in formulating effective treatment strategies for individuals facing these challenges.
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Affiliation(s)
- Maki Saito
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan; Department of Pediatrics, Jikei University School of Medicine, Japan
| | - Hiroki Nishi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan
| | - Shin-Ichiro Takahashi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan
| | - Fumihiko Hakuno
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan.
| | - Ichiro Miyata
- Department of Pediatrics, Jikei University School of Medicine, Japan
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Wang J, Liu X, Lan Y, Que T, Li J, Yue B, Fan Z. DNA methylation and transcriptome analysis reveal epigenomic differences among three macaque species. Evol Appl 2024; 17:e13604. [PMID: 38343783 PMCID: PMC10853583 DOI: 10.1111/eva.13604] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/28/2024] Open
Abstract
Macaques (genus Macaca) are the most widely distributed non-human primates, and their evolutionary history, gene expression profiles, and genetic differences have been extensively studied. However, the DNA methylomes of macaque species are not available in public databases, which hampers understanding of epigenetic differences among macaque species. Epigenetic modifications can potentially affect development, physiology, behavior, and evolution. Here, we investigated the methylation patterns of the Tibetan macaque (M. thibetana; TM), Chinese rhesus macaque (M. mulatta lasiota; CR), and crab-eating macaque (M. fascicularis; CE) through whole-genome bisulfite sequencing from peripheral blood. We compared genome-wide methylation site information for the three species. We identified 12,128 (CR vs. CE), 59,165 (CR vs. TM), and 39,751 (CE vs. TM) differentially methylated regions (DMRs) in the three macaques. Furthermore, we obtained the differentially expressed genes (DEGs) among the three macaque species. The differences between CR and CE were smaller at both the methylome and transcriptome levels than compared with TM (CR vs. TM and CE vs. TM). We also found a change in the density of single nucleotide mutations in DMRs relative to their flanking regions, indicating a potential mechanism through which genomic alterations may modulate methylation landscapes, thereby influencing the transcriptome. Functional enrichment analyses showed the DMR-related genes were enriched in developmental processes and neurological functions, such as the growth hormone-related pathway, insulin secretion pathway, thyroid hormone synthesis pathway, morphine addiction, and GABAergic synapses. These differences may be associated with variations in physiology and habitat among the macaques. Our study provides one of the first genome-wide comparisons of genetic, gene expression, and epigenetic variations across different macaques. Our results should facilitate further research on comparative genomic and genetic differences in macaque species.
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Affiliation(s)
- Jiao Wang
- Key Laboratory of Bioresources and Eco‐Environment (Ministry of Education), College of Life SciencesSichuan UniversitySichuanChengduChina
| | - Xuyuan Liu
- Key Laboratory of Bioresources and Eco‐Environment (Ministry of Education), College of Life SciencesSichuan UniversitySichuanChengduChina
| | - Yue Lan
- Sichuan Key Laboratory of Conservation Biology on Endangered Wildlife, College of Life SciencesSichuan UniversitySichuanChengduChina
| | - Tengcheng Que
- Terrestrial Wildlife Rescue and Epidemic Diseases Surveillance Center of GuangxiGuangxiNanningChina
- Faculty of Data ScienceCity University of MacauMacauTaipaChina
| | - Jing Li
- Key Laboratory of Bioresources and Eco‐Environment (Ministry of Education), College of Life SciencesSichuan UniversitySichuanChengduChina
| | - Bisong Yue
- Sichuan Key Laboratory of Conservation Biology on Endangered Wildlife, College of Life SciencesSichuan UniversitySichuanChengduChina
| | - Zhenxin Fan
- Key Laboratory of Bioresources and Eco‐Environment (Ministry of Education), College of Life SciencesSichuan UniversitySichuanChengduChina
- Sichuan Key Laboratory of Conservation Biology on Endangered Wildlife, College of Life SciencesSichuan UniversitySichuanChengduChina
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Grimberg A, Hawkes CP. Growth Hormone Treatment for Non-GHD Disorders: Excitement Tempered by Biology. J Clin Endocrinol Metab 2024; 109:e442-e454. [PMID: 37450564 PMCID: PMC10795916 DOI: 10.1210/clinem/dgad417] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
The success of growth hormone (GH) replacement in children with classical GH deficiency has led to excitement that other causes of short stature may benefit similarly. However, clinical experience has shown less consistent and generally less dramatic effects on adult height, perhaps not surprising in light of increased understanding of GH and growth plate biology. Nonetheless, clinical demand for GH treatment continues to grow. Upon the 20th anniversary of the US Food and Drug Administration's approval of GH treatment for idiopathic short stature, this review will consider the factors underlying the expansion of GH treatment, the biological mechanisms of GH action, the non-GH-deficient uses of GH as a height-promoting agent, biological constraints to GH action, and future directions.
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Affiliation(s)
- Adda Grimberg
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Colin P Hawkes
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- INFANT Research Centre, University College Cork, Cork T12 DC4A, Ireland
- Department of Paediatrics and Child Health, University College Cork, Cork T12 R229, Ireland
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12
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Javvaji PK, Francis JR, Dhali A, Kolte AP, Mech A, Roy SC, Mishra A. Interleukin-6 stimulates in vitro development of late-stage ovine embryos. J Reprod Immunol 2023; 159:104133. [PMID: 37647796 DOI: 10.1016/j.jri.2023.104133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/29/2023] [Accepted: 08/12/2023] [Indexed: 09/01/2023]
Abstract
The effect of interleukin-6 (IL-6) supplementation during the different phases of in vitro embryo culturing (IVC) on embryo development and embryonic gene expression was studied in ovine. IL-6 was added to IVC medium during the late phases (72-192 h; 5, 10, and 25 ng/ml IL-6) or entire period (0-192 h; 10 ng/ml IL-6) of IVC to determine its effect on embryo development. Further, the effect of IL-6 (10 ng/ml) supplementation at the 72 h of IVC on gene expressions associated with JAK/STAT signalling and pluripotency in 8-16 cell embryos (1 h post-supplementation) and compact morulae (48 h post-supplementation), and apoptosis and primitive endoderm (PrE) development in compact morulae was investigated. The supplementation of 10 ng/ml IL-6 during the late phases of IVC significantly (P < 0.05) increased blastocyst formation (35.2 ± 1.52%) compared to the control (21.1 ± 1.11%), and 5 ng/ml (25.9 ± 2.98%) or 25 ng/ml (16.5 ± 0.73%) IL-6 groups. Conversely, IL-6 (10 ng/ml) treatment throughout the IVC period significantly (P < 0.05) decreased the rate of cleavage (55.4 ± 1.57%) and blastocyst formation (14.5 ± 1.28%) compared to the control group (65.8 ± 1.35% and 21.5 ± 0.97%, respectively). In 8-16 cell embryos and compact morulae, the IL-6 treatment significantly (P < 0.05) affected the expression of genes associated with JAK/STAT signalling and pluripotency. Further, the treatment significantly (P < 0.05) downregulated BAX and CASP3, and upregulated GATA6 expression in compact morulae. In conclusion, IL-6 supplementation affected the in vitro development of ovine embryos in a dose- and time-dependent manner. The beneficial effect of IL-6 on the development of late-stage embryos was mediated through the changes in gene expressions associated with JAK/STAT signalling, pluripotency, apoptosis and PrE development.
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Affiliation(s)
- Pradeep Krishna Javvaji
- ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Hosur Road, Bengaluru 560 030, India
| | - Joseph Rabinson Francis
- ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Hosur Road, Bengaluru 560 030, India
| | - Arindam Dhali
- ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Hosur Road, Bengaluru 560 030, India.
| | - Atul P Kolte
- ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Hosur Road, Bengaluru 560 030, India
| | - Anjumoni Mech
- ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Hosur Road, Bengaluru 560 030, India
| | - Sudhir C Roy
- ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Hosur Road, Bengaluru 560 030, India
| | - Ashish Mishra
- ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Hosur Road, Bengaluru 560 030, India
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13
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Voltan G, Mazzeo P, Regazzo D, Scaroni C, Ceccato F. Role of Estrogen and Estrogen Receptor in GH-Secreting Adenomas. Int J Mol Sci 2023; 24:9920. [PMID: 37373068 DOI: 10.3390/ijms24129920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/17/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Acromegaly is a rare disease with several systemic complications that may lead to increased overall morbidity and mortality. Despite several available treatments, ranging from transsphenoidal resection of GH-producing adenomas to different medical therapies, complete hormonal control is not achieved in some cases. Some decades ago, estrogens were first used to treat acromegaly, resulting in a significant decrease in IGF1 levels. However, due to the consequent side effects of the high dose utilized, this treatment was later abandoned. The evidence that estrogens are able to blunt GH activity also derives from the evidence that women with GH deficiency taking oral estro-progestins pills need higher doses of GH replacement therapy. In recent years, the role of estrogens and Selective Estrogens Receptor Modulators (SERMs) in acromegaly treatment has been re-evaluated, especially considering poor control of the disease under first- and second-line medical treatment. In this review, we analyze the state of the art concerning the impact of estrogen and SERMs on the GH/IGF1 axis, focusing on molecular pathways and the possible implications for acromegaly treatment.
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Affiliation(s)
- Giacomo Voltan
- Department of Medicine (DIMED), University of Padova, Via Giustiniani 2, 35128 Padova, Italy
- Endocrinology Unit, Padova University Hospital, Via Ospedale Civile 105, 35128 Padova, Italy
| | - Pierluigi Mazzeo
- Department of Medicine (DIMED), University of Padova, Via Giustiniani 2, 35128 Padova, Italy
- Endocrinology Unit, Padova University Hospital, Via Ospedale Civile 105, 35128 Padova, Italy
| | - Daniela Regazzo
- Department of Medicine (DIMED), University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Carla Scaroni
- Department of Medicine (DIMED), University of Padova, Via Giustiniani 2, 35128 Padova, Italy
- Endocrinology Unit, Padova University Hospital, Via Ospedale Civile 105, 35128 Padova, Italy
| | - Filippo Ceccato
- Department of Medicine (DIMED), University of Padova, Via Giustiniani 2, 35128 Padova, Italy
- Endocrinology Unit, Padova University Hospital, Via Ospedale Civile 105, 35128 Padova, Italy
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14
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Kanno H, Matsumoto S, Yoshizumi T, Nakahara K, Kubo A, Murata H, Shuin T, U HS. Role of SOCS and VHL Proteins in Neuronal Differentiation and Development. Int J Mol Sci 2023; 24:ijms24043880. [PMID: 36835292 PMCID: PMC9960776 DOI: 10.3390/ijms24043880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.
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Affiliation(s)
- Hiroshi Kanno
- Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan
- Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan
- Correspondence: ; Tel.: +81-3-5242-5800
| | - Shutaro Matsumoto
- Department of Neurosurgery, School of Medicine, Yokohama City University, Yokohama 232-0024, Japan
- Department of Neurosurgery, Asahi Hospital, Tokyo 121-0078, Japan
| | - Tetsuya Yoshizumi
- Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan
| | - Kimihiro Nakahara
- Department of Neurosurgery, International University of Health and Welfare, Atami 413-0012, Japan
| | | | - Hidetoshi Murata
- Department of Neurosurgery, St. Mariannna Medical University, Kawasaki 216-8511, Japan
| | - Taro Shuin
- Kochi Medical School Hospital, Nangoku 783-0043, Japan
| | - Hoi-Sang U
- Department of Electrical Engineering, University of California San Diego, San Diego, CA 92093, USA
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15
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Systematic Bayesian posterior analysis guided by Kullback-Leibler divergence facilitates hypothesis formation. J Theor Biol 2023; 558:111341. [PMID: 36335999 DOI: 10.1016/j.jtbi.2022.111341] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/24/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022]
Abstract
Bayesian inference produces a posterior distribution for the parameters of a mathematical model that can be used to guide the formation of hypotheses; specifically, the posterior may be searched for evidence of alternative model hypotheses, which serves as a starting point for hypothesis formation and model refinement. Previous approaches to search for this evidence are largely qualitative and unsystematic; further, demonstrations of these approaches typically stop at hypothesis formation, leaving the questions they raise unanswered. Here, we introduce a Kullback-Leibler (KL) divergence-based ranking to expedite Bayesian hypothesis formation and investigate the hypotheses it generates, ultimately generating novel, biologically significant insights. Our approach uses KL divergence to rank parameters by how much information they gain from experimental data. Subsequently, rather than searching all model parameters at random, we use this ranking to prioritize examining the posteriors of the parameters that gained the most information from the data for evidence of alternative model hypotheses. We test our approach with two examples, which showcase the ability of our approach to systematically uncover different types of alternative hypothesis evidence. First, we test our KL divergence ranking on an established example of Bayesian hypothesis formation. Our top-ranked parameter matches the one previously identified to produce alternative hypotheses. In the second example, we apply our ranking in a novel study of a computational model of prolactin-induced JAK2-STAT5 signaling, a pathway that mediates beta cell proliferation. Within the top 3 ranked parameters (out of 33), we find a bimodal posterior revealing two possible ranges for the prolactin receptor degradation rate. We go on to refine the model, incorporating new data and determining which degradation rate is most plausible. Overall, while the effectiveness of our approach depends on having a properly formulated prior and on the form of the posterior distribution, we demonstrate that our approach offers a novel and generalizable quantitative framework for Bayesian hypothesis formation and use it to produce a novel, biologically-significant insight into beta cell signaling.
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16
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Huang J, Walters TD. Growth Impairment in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:151-172. [DOI: 10.1007/978-3-031-14744-9_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Du Y, Xu X, Lv S, Liu H, Sun H, Wu J. SOCS7/HuR/FOXM1 signaling axis inhibited high-grade serous ovarian carcinoma progression. J Exp Clin Cancer Res 2022; 41:185. [PMID: 35624501 PMCID: PMC9137060 DOI: 10.1186/s13046-022-02395-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/12/2022] [Indexed: 12/01/2022] Open
Abstract
Background High-grade serous ovarian carcinoma (HGSOC) is clinically dominant and accounts for ~ 80% deaths in all types of ovarian cancer. The delayed diagnosis, rapid development, and wide dissemination of HGSOC collectively contribute to its high mortality rate and poor prognosis in the patients. Suppressors of cytokine signaling 7 (SOCS7) can regulate cytokine signaling and participate in cell cycle arrest and regulation of cell proliferation, which might also be involved in carcinogenesis. Here, we designated to investigate the functions and mechanisms of SOCS7 in HGSOC. Methods The clinical correlation between SOCS7 and HGSOC was examined by both bioinformatics and analysis of tissue samples in patients. Gain/Loss-of-function examinations were carried out to assess the effectiveness of SOCS7 in cell viability, cell cycle, and tumor growth of HGSOC. Furthermore, the underlying mechanisms were explored by identifying the downstream proteins and their interactions via proteomics analysis and immunoprecipitation. Results The expression of SOCS7, which was decreased in HGSOC tissues, was correlated with the clinical pathologic characteristics and overall survival of HGSOC patients. SOCS7 acted as a HGSOC suppressor by inhibiting cancer cell viability and tumor growth in vivo. The anti-HGSOC mechanism involves SOCS7’s regulatory effect on HuR by mediating its ubiquitination, the regulation of FOXM1 mRNA by HuR, as well as the interplays among these three clinically relevant factors. Conclusions The SOCS7 correlates with HGSOC and suppresses its tumorigenesis through regulating HuR and FOXM1, which also suggests that SOCS7 is a prospective biomarker for the clinical management of ovarian cancer, especially HGSOC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02395-1.
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Fei H, Cheng Y, Zhang H, Yu X, Yi S, Huang M, Yang S. Effect of Autolyzed Yarrowia lipolytica on the Growth Performance, Antioxidant Capacity, Intestinal Histology, Microbiota, and Transcriptome Profile of Juvenile Largemouth Bass (Micropterus salmoides). Int J Mol Sci 2022; 23:ijms231810780. [PMID: 36142687 PMCID: PMC9503160 DOI: 10.3390/ijms231810780] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 12/03/2022] Open
Abstract
The improper components of formulated feed can cause the intestinal dysbiosis of juvenile largemouth bass and further affect fish health. A 28 day feeding trial was conducted to investigate the effect of partially replacing fish meal (FM) with autolyzed Yarrowia lipolytica (YL) on juvenile largemouth bass (Micropterus salmoides). We considered four diets—control, YL25, YL50, and YL75—in which 0%, 25%, 50%, and 75% of the FM content, respectively, was replaced with YL. According to results, the weight gain rate (WGR) and specific growth rate (SGR) of the fish with the YL25 and YL50 diets were significantly higher than the WGR and SGR with the control diet, while the YL75 diet significantly reduced fish growth and antioxidant enzymes activities, and shortened the villus height in the intestinal mucosa. The 16S rRNA analysis of the intestinal microbiota showed that the relative abundance of Mycoplasma was significantly increased with the YL25 and YL50 diets, while the Enterobacteriacea content was increased with the YL75 diet. Moreover, our transcriptome analysis revealed that certain differentially expressed genes (DEGs) that are associated with growth, metabolism, and immunity were modulated by YL inclusion treatment. Dietary YL25 and YL50 significantly reduced the mRNA level of ERBB receptor feedback inhibitor 1 (errfi1) and dual-specificity phosphatases (dusp), while the expression of the suppressor of cytokine signaling 1 (socs1), the transporter associated with antigen processing 2 subunit type a (tap2a), and the major histocompatibility complex class I-related gene (MHC-I-l) were sharply increased with YL75 treatment. We determined that the optimum dose of dietary YL required for maximum growth without any adverse influence on intestinal health was 189.82 g/kg (with 31.63% of the fishmeal replaced by YL), while an excessive substitution of YL for fishmeal led to suppressed growth and antioxidant capacity, as well as intestinal damage for juvenile largemouth bass.
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Affiliation(s)
- Hui Fei
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Yan Cheng
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Huimin Zhang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Xiang Yu
- Zhejiang Development &Planning Institute, Hangzhou 310012, China
| | - Shunfa Yi
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Mengmeng Huang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Shun Yang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
- Correspondence: ; Tel.: +86-0571-8684-3199
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Yu C, Fan Y, Zhang Y, Liu L, Guo G. LINC00893 inhibits the progression of prostate cancer through miR-3173-5p/SOCS3/JAK2/STAT3 pathway. Cancer Cell Int 2022; 22:228. [PMID: 35818076 PMCID: PMC9275192 DOI: 10.1186/s12935-022-02637-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 06/17/2022] [Indexed: 11/21/2022] Open
Abstract
Background Prostate cancer (PCa) is one of the most common malignant tumors in the male urinary system. In recent years, the morbidity and mortality of PCa have been increasing due to the limited effects of existing treatment strategies. Long non-coding RNA (lncRNA) LINC00893 was reported to inhibit the proliferation and metastasis of papillary thyroid cancer cells, but its role in PCa has not been reported. This study aims to investigate the role and underlying mechanism of LINC00893 in regulating the progression of PCa cells. Methods We first compared LINC00893 expression levels between PCa tissues and normal prostate tissues through TCGA database. The relative LINC00893 expression levels were further validated in 66 pairs of PCa tissues and para-cancerous normal tissues, as well as in PCa cell lines. Gain-of-function experiment was performed by transfecting PCa cell with LINC00893 expression vector, and CCK (Cell count kit)-8, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, colony information and transwell assays were conducted to assess the functional phenotypes. Dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP) and RNA pull-down assays were performed to evaluate the molecular interactions. Results LINC00893 was downregulated in PCa tissues and cell lines, and patients with low expression of LINC00893 were associated with a poorer overall survival rate. LINC00893 overexpression hindered the proliferation, epithelial-mesenchymal transition (EMT) as well as the migratory ability of PCa cells, and suppressed the tumorigenesis of PCa cells in nude mice. We further demonstrated that LINC00893 acted as a sponge for miR-3173-5p and inhibited its activity, which in turn regulated the suppressor of cytokine signaling 3 (SOCS3)/Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. Conclusions Our study demonstrated that LINC00893 suppresses the progression of PCa cells through targeting miR-3173-5p/SOCS3/JAK2/STAT3 axis. Our data uncovers a novel tumor-suppressor role of LINC00893 in PCa, which may serve as a potential strategy for targeted therapy in PCa. Grapical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02637-4.
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Affiliation(s)
- Chuigong Yu
- Department of Urology, The Third Medical Center, Chinese People's Liberation Army General Hospital, No. 69, Yongding Road, Haidian District, Beijing, 100039, China
| | - Yu Fan
- Department of Urology, The Third Medical Center, Chinese People's Liberation Army General Hospital, No. 69, Yongding Road, Haidian District, Beijing, 100039, China
| | - Yu Zhang
- Department of Urology, The Third Medical Center, Chinese People's Liberation Army General Hospital, No. 69, Yongding Road, Haidian District, Beijing, 100039, China
| | - Lupeng Liu
- Department of Urology, The Third Medical Center, Chinese People's Liberation Army General Hospital, No. 69, Yongding Road, Haidian District, Beijing, 100039, China
| | - Gang Guo
- Department of Urology, The Third Medical Center, Chinese People's Liberation Army General Hospital, No. 69, Yongding Road, Haidian District, Beijing, 100039, China.
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20
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Penn DJ, Zala SM, Luzynski KC. Regulation of Sexually Dimorphic Expression of Major Urinary Proteins. Front Physiol 2022; 13:822073. [PMID: 35431992 PMCID: PMC9008510 DOI: 10.3389/fphys.2022.822073] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/21/2022] [Indexed: 11/15/2022] Open
Abstract
Male house mice excrete large amounts of protein in their urinary scent marks, mainly composed of Major Urinary Proteins (MUPs), and these lipocalins function as pheromones and pheromone carriers. Here, we review studies on sexually dimorphic MUP expression in house mice, including the proximate mechanisms controlling MUP gene expression and their adaptive functions. Males excrete 2 to 8 times more urinary protein than females, though there is enormous variation in gene expression across loci in both sexes. MUP expression is dynamically regulated depending upon a variety of factors. Males regulate MUP expression according to social status, whereas females do not, and males regulate expression depending upon health and condition. Male-biased MUP expression is regulated by pituitary secretion of growth hormone (GH), which binds receptors in the liver, activating the JAK2-STAT5 signaling pathway, chromatin accessibility, and MUP gene transcription. Pulsatile male GH secretion is feminized by several factors, including caloric restriction, microbiota depletion, and aging, which helps explain condition-dependent MUP expression. If MUP production has sex-specific fitness optima, then this should generate sexual antagonism over allelic expression (intra-locus sexual conflict) selectively favoring sexually dimorphic expression. MUPs influence the sexual attractiveness of male urinary odor and increased urinary protein excretion is correlated with the reproductive success of males but not females. This finding could explain the selective maintenance of sexually dimorphic MUP expression. Producing MUPs entails energetic costs, but increased excretion may reduce the net energetic costs and predation risks from male scent marking as well as prolong the release of chemical signals. MUPs may also provide physiological benefits, including regulating metabolic rate and toxin removal, which may have sex-specific effects on survival. A phylogenetic analysis on the origins of male-biased MUP gene expression in Mus musculus suggests that this sexual dimorphism evolved by increasing male MUP expression rather than reducing female expression.
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Affiliation(s)
- Dustin J. Penn
- Department of Interdisciplinary Life Sciences, Konrad Lorenz Institute of Ethology, University of Veterinary Medicine Vienna, Vienna, Austria
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21
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Qian Y, Berryman DE, Basu R, List EO, Okada S, Young JA, Jensen EA, Bell SRC, Kulkarni P, Duran-Ortiz S, Mora-Criollo P, Mathes SC, Brittain AL, Buchman M, Davis E, Funk KR, Bogart J, Ibarra D, Mendez-Gibson I, Slyby J, Terry J, Kopchick JJ. Mice with gene alterations in the GH and IGF family. Pituitary 2022; 25:1-51. [PMID: 34797529 PMCID: PMC8603657 DOI: 10.1007/s11102-021-01191-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/21/2021] [Indexed: 01/04/2023]
Abstract
Much of our understanding of GH's action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor. The ability to stay current with the various genetically manipulated mouse lines within the realm of GH/IGF1 research has been daunting. As such, this review attempts to consolidate and summarize the literature related to the initial characterization of many of the known gene-manipulated mice relating to the actions of GH, PRL and IGF1. We have organized the mouse lines by modifications made to constituents of the GH/IGF1 family either upstream or downstream of GHR or to the GHR itself. Available data on the effect of altered gene expression on growth, GH/IGF1 levels, body composition, reproduction, diabetes, metabolism, cancer, and aging are summarized. For the ease of finding this information, key words are highlighted in bold throughout the main text for each mouse line and this information is summarized in Tables 1, 2, 3 and 4. Most importantly, the collective data derived from and reported for these mice have enhanced our understanding of GH action.
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Affiliation(s)
- Yanrong Qian
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Darlene E Berryman
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Edward O List
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Shigeru Okada
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Pediatrics, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Jonathan A Young
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Elizabeth A Jensen
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Translational Biomedical Sciences Doctoral Program, Ohio University, Athens, OH, USA
| | - Stephen R C Bell
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Prateek Kulkarni
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | | | - Patricia Mora-Criollo
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Translational Biomedical Sciences Doctoral Program, Ohio University, Athens, OH, USA
| | - Samuel C Mathes
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Alison L Brittain
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | - Mat Buchman
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Emily Davis
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | - Kevin R Funk
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, USA
| | - Jolie Bogart
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Diego Ibarra
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Chemistry and Biochemistry, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Isaac Mendez-Gibson
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- College of Health Sciences and Professions, Ohio University, Athens, OH, USA
| | - Julie Slyby
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Joseph Terry
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA.
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
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22
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Linossi EM, Li K, Veggiani G, Tan C, Dehkhoda F, Hockings C, Calleja DJ, Keating N, Feltham R, Brooks AJ, Li SS, Sidhu SS, Babon JJ, Kershaw NJ, Nicholson SE. Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nat Commun 2021; 12:7032. [PMID: 34857742 PMCID: PMC8640019 DOI: 10.1038/s41467-021-26983-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 10/28/2021] [Indexed: 11/09/2022] Open
Abstract
Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling.
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Affiliation(s)
- Edmond M Linossi
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Kunlun Li
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Gianluca Veggiani
- The Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Cyrus Tan
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Farhad Dehkhoda
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Colin Hockings
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Dale J Calleja
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Narelle Keating
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Rebecca Feltham
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Andrew J Brooks
- The University of Queensland Diamantina Institute, Woolloongabba, QLD, 4102, Australia
| | - Shawn S Li
- Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada
| | - Sachdev S Sidhu
- The Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Jeffrey J Babon
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Nadia J Kershaw
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
| | - Sandra E Nicholson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
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23
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Wei W, Liu Z, Zhang C, Khoriaty R, Zhu M, Zhang B. A common human missense mutation of vesicle coat protein SEC23B leads to growth restriction and chronic pancreatitis in mice. J Biol Chem 2021; 298:101536. [PMID: 34954140 PMCID: PMC8760524 DOI: 10.1016/j.jbc.2021.101536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/17/2021] [Accepted: 12/18/2021] [Indexed: 11/16/2022] Open
Affiliation(s)
- Wei Wei
- Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio, USA
| | - Zhigang Liu
- Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio, USA
| | - Chao Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rami Khoriaty
- Departments of Internal Medicine, Cell and Developmental Biology and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Min Zhu
- Department of Pathology, Xinjiang Key Laboratory of Clinical Genetic Testing and Biomedical Information, Karamay Central Hospital, Karamay, China.
| | - Bin Zhang
- Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio, USA.
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Kageyama K, Iwasaki Y, Daimon M. Hypothalamic Regulation of Corticotropin-Releasing Factor under Stress and Stress Resilience. Int J Mol Sci 2021; 22:ijms222212242. [PMID: 34830130 PMCID: PMC8621508 DOI: 10.3390/ijms222212242] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023] Open
Abstract
This review addresses the molecular mechanisms of corticotropin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience. CRF in the hypothalamus plays a central role in regulating the stress response. CRF stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates glucocorticoid secretion from the adrenal glands. Glucocorticoids are essential for stress coping, stress resilience, and homeostasis. The activated hypothalamic-pituitary-adrenal axis is suppressed by the negative feedback from glucocorticoids. Glucocorticoid-dependent repression of cAMP-stimulated Crf promoter activity is mediated by both the negative glucocorticoid response element and the serum response element. Conversely, the inducible cAMP-early repressor can suppress the stress response via inhibition of the cAMP-dependent Crf gene, as can the suppressor of cytokine signaling-3 in the hypothalamus. CRF receptor type 1 is mainly involved in a stress response, depression, anorexia, and seizure, while CRF receptor type 2 mediates “stress coping” mechanisms such as anxiolysis in the brain. Differential effects of FK506-binding immunophilins, FKBP4 and FKBP5, contribute to the efficiency of glucocorticoids under stress resilience. Together, a variety of factors contribute to stress resilience. All these factors would have the differential roles under stress resilience.
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Affiliation(s)
- Kazunori Kageyama
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Aomori, Japan;
- Correspondence: ; Tel.: +81-172-39-5062
| | - Yasumasa Iwasaki
- Department of Clinical Nutrition Management Nutrition Course, Faculty of Health Science, Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka 510-0293, Mie, Japan;
| | - Makoto Daimon
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Aomori, Japan;
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Zhang X, Zhuang Y, Qin T, Chang M, Ji X, Wang N, Zhang Z, Zhou H, Wang Q, Li JZ. Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway. Metabolism 2021; 122:154823. [PMID: 34197875 DOI: 10.1016/j.metabol.2021.154823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/03/2021] [Accepted: 06/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatic gluconeogenesis plays a crucial role in maintaining blood glucose homeostasis in mammals. Globe knockout of suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown resistant to high-fat-diet (HFD)-induced hepatic steatosis with impaired glucose tolerance in mice. However, the underlying mechanism of SOCS2 regulates hepatic glucose homeostasis still undefined. In the present study, we demonstrated that the hepatic SOCS2 expression is markedly reduced in fasted C57BL/6 J mice or db/db mice. Moreover, hepatic SOCS2 expression levels are induced by metformin treatment. Ablation of SOCS2 attenuates suppressing effects of metformin on gluconeogenesis in hepatocytes. Gain- and loss-of-function studies indicated that SOCS2 regulates hepatic gluconeogenic genes expression and glucose output by mediating JAK2/STAT5 signalling pathway in db/db mice. Mechanistically, we observed that SOCS2 inactivates STAT5 by attenuating the interaction between JAK2 and STAT5, which in turn reduces hepatic gluconeogenesis. The present study reveals a critical role of SOCS2 in regulating hepatic gluconeogenesis. The inhibitory effect of metformin on gluconeogenesis is mediated, at least in part, by upregulating SOCS2 and therefore reducing hepatic gluconeogenic genes expression. SOCS2 may represent a new therapeutic target for the treatment of diabetes.
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Affiliation(s)
- Xu Zhang
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China
| | - Yuan Zhuang
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China
| | - Tian Qin
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China
| | - Meijia Chang
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China
| | - Xuetao Ji
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China
| | - Ning Wang
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China
| | - Zhilei Zhang
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China
| | - Hongwen Zhou
- Department of Endocrinology, The First affiliated Hospital of Nanjing Medical University, Nanijing 210029, China
| | - Qian Wang
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China.
| | - John Zhong Li
- The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China.
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Zeng H, Li L, Gao Y, Wu G, Hou Z, Liu S. Long noncoding RNA UCA1 regulates HCV replication and antiviral response via miR-145-5p/SOCS7/IFN pathway. Int J Biol Sci 2021; 17:2826-2840. [PMID: 34345210 PMCID: PMC8326114 DOI: 10.7150/ijbs.59227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 06/21/2021] [Indexed: 12/25/2022] Open
Abstract
Hepatitis C virus (HCV) infection involves a variety of viral and host factors, which leads to the dysregulation of number of relevant genes including long noncoding RNAs (LncRNAs). LncRNA urothelial carcinoma-associated 1 (UCA1) has been reported to be upregulated in HCV-infected individuals. In a bid to elucidate on the contribution of UCA1 on HCV replication, we infected Huh7.5 cells with cell culture-derived HCV and found that UCA1 expression was elevated in time- and dose-dependent manners. Functionally, UCA1 knockdown by siRNA upregulated interferon (IFN) responses, thereby increasing the expression of interferon-stimulating genes (ISGs), and subsequently suppressing HCV replication. Bioinformatics analysis and experimental results indicated that, functioning as competitive endogenous RNA, UCA1 could sponge microRNA (miR)-145-5p, which targeted suppressor of cytokine signaling 7 (SOCS7) mRNA and subsequently mediated SOCS7 silencing. Moreover, SOCS7 protein exerted an inhibitory effect on IFN responses, thereby facilitating HCV replication. Taken together, at first, our findings demonstrate that UCA1 can counteract the expression of miR-145-5p, thereby upregulating the level of SOCS7, and in turn leading to the suppression of antiviral response in Huh7.5 cells.
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Affiliation(s)
- Haiyan Zeng
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Lei Li
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100010, China
| | - Yi Gao
- Department of Infectious Disease, the Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, China
| | - Guojun Wu
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
| | - Zhouhua Hou
- Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shuiping Liu
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
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27
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Boitard C, Michel A, Ménager C, Griffete N. Protein Denaturation Through the Use of Magnetic Molecularly Imprinted Polymer Nanoparticles. Molecules 2021; 26:molecules26133980. [PMID: 34210027 PMCID: PMC8272029 DOI: 10.3390/molecules26133980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 11/16/2022] Open
Abstract
The inhibition of the protein function for therapeutic applications remains challenging despite progress these past years. While the targeting application of molecularly imprinted polymer are in their infancy, no use was ever made of their magnetic hyperthermia properties to damage proteins when they are coupled to magnetic nanoparticles. Therefore, we have developed a facile and effective method to synthesize magnetic molecularly imprinted polymer nanoparticles using the green fluorescent protein (GFP) as the template, a bulk imprinting of proteins combined with a grafting approach onto maghemite nanoparticles. The hybrid material exhibits very high adsorption capacities and very strong affinity constants towards GFP. We show that the heat generated locally upon alternative magnetic field is responsible of the decrease of fluorescence intensity.
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28
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Sun M, Tang C, Liu J, Jiang W, Yu H, Dong F, Huang C, Rixiati Y. Comprehensive analysis of suppressor of cytokine signaling proteins in human breast Cancer. BMC Cancer 2021; 21:696. [PMID: 34120621 PMCID: PMC8201682 DOI: 10.1186/s12885-021-08434-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 06/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA). Methods The gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA). Results Data related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro. Conclusions SOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08434-y.
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Affiliation(s)
- Mingyu Sun
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Chuangang Tang
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Jun Liu
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Wenli Jiang
- Department of Biochemistry and Molecular Biology, College of Basic Medical, Navy Medical University, Shanghai, 200433, China
| | - Haifeng Yu
- Department of General Surgery, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Fang Dong
- Department of Vascular Surgery, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Caiguo Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical, Navy Medical University, Shanghai, 200433, China
| | - Youlutuziayi Rixiati
- Department of Pathology, Soochow University Medical School, Suzhou, 215123, China.
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Goldfarb CN, Waxman DJ. Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs. BMC Genomics 2021; 22:212. [PMID: 33761883 PMCID: PMC7992343 DOI: 10.1186/s12864-021-07478-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 02/24/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND While nuclear transcription and RNA processing and localization are well established for protein coding genes (PCGs), these processes are poorly understood for long non-coding (lnc)RNAs. Here, we characterize global patterns of transcript expression, maturation and localization for mouse liver RNA, including more than 15,000 lncRNAs. PolyA-selected liver RNA was isolated and sequenced from four subcellular fractions (chromatin, nucleoplasm, total nucleus, and cytoplasm), and from the chromatin-bound fraction without polyA selection. RESULTS Transcript processing, determined from normalized intronic to exonic sequence read density ratios, progressively increased for PCG transcripts in going from the chromatin-bound fraction to the nucleoplasm and then on to the cytoplasm. Transcript maturation was similar for lncRNAs in the chromatin fraction, but was significantly lower in the nucleoplasm and cytoplasm. LncRNA transcripts were 11-fold more likely to be significantly enriched in the nucleus than cytoplasm, and 100-fold more likely to be significantly chromatin-bound than nucleoplasmic. Sequencing chromatin-bound RNA greatly increased the sensitivity for detecting lowly expressed lncRNAs and enabled us to discover and localize hundreds of novel regulated liver lncRNAs, including lncRNAs showing sex-biased expression or responsiveness to TCPOBOP a xenobiotic agonist ligand of constitutive androstane receptor (Nr1i3). CONCLUSIONS Integration of our findings with prior studies and lncRNA annotations identified candidate regulatory lncRNAs for a variety of hepatic functions based on gene co-localization within topologically associating domains or transcription divergent or antisense to PCGs associated with pathways linked to hepatic physiology and disease.
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Affiliation(s)
- Christine N Goldfarb
- Department of Biology and Bioinformatics Program, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA
| | - David J Waxman
- Department of Biology and Bioinformatics Program, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA.
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Chhabra Y, Lee CMM, Müller AF, Brooks AJ. GHR signalling: Receptor activation and degradation mechanisms. Mol Cell Endocrinol 2021; 520:111075. [PMID: 33181235 DOI: 10.1016/j.mce.2020.111075] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 12/21/2022]
Abstract
Growth hormone (GH) actions via initiating cell signalling through the GH receptor (GHR) are important for many physiological processes, in addition to its well-known role in regulating growth. The activation of JAK-STAT signalling by GH is well characterized, however knowledge on GH activation of SRC family kinases (SFKs) is still limited. In this review we summarise the collective knowledge on the activation, regulation, and downstream signalling of GHR. We highlight studies on GH activation of SFKs and the important outcome of this signalling pathway with a focus on the different degradation mechanisms that can regulate GHR availability since this is an area that warrants further study considering its role in tumour progression.
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Affiliation(s)
- Yash Chhabra
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21231, USA
| | - Christine M M Lee
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia
| | - Alexandra Franziska Müller
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia
| | - Andrew J Brooks
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
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Frank SJ. Classical and novel GH receptor signaling pathways. Mol Cell Endocrinol 2020; 518:110999. [PMID: 32835785 PMCID: PMC7799394 DOI: 10.1016/j.mce.2020.110999] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/12/2020] [Accepted: 08/17/2020] [Indexed: 12/16/2022]
Abstract
In this review, I summarize historical and recent features of the classical pathways activated by growth hormone (GH) through the cell surface GH receptor (GHR). GHR is a cytokine receptor superfamily member that signals by activating the non-receptor tyrosine kinase, JAK2, and members of the Src family kinases. Activation of the GHR engages STATs, PI3K, and ERK pathways, among others, and details of these now-classical pathways are presented. Modulating elements, including the SOCS proteins, phosphatases, and regulated GHR metalloproteolysis, are discussed. In addition, a novel physical and functional interaction of GHR with IGF-1R is summarized and discussed in terms of its mechanisms, consequences, and physiological and therapeutic implications.
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Affiliation(s)
- Stuart J Frank
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, 1720 2nd Avenue South, BDB 485, AL, 35294-0012, USA; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, AL, 35233, USA.
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32
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Gutiérrez M. Activating mutations of STAT3: Impact on human growth. Mol Cell Endocrinol 2020; 518:110979. [PMID: 32818584 DOI: 10.1016/j.mce.2020.110979] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023]
Abstract
The signal transducer and activator of transcription (STAT) 3 is the most ubiquitous member of the STAT family and fulfills fundamental functions in immune and non-immune cells. Mutations in the STAT3 gene lead to different human diseases. Germline STAT3 activating or gain-of-function (GOF) mutations result in early-onset multiorgan autoimmunity, lymphoproliferation, recurrent infections and short stature. Since the first description of the disease, the clinical manifestations of STAT3 GOF mutations have expanded considerably. However, due to the complexity of immunological characteristics in patients carrying STAT3 GOF mutations, most of attention was focused on the immune alterations. This review summarizes current knowledge on STAT3 GOF mutations with special focus on the growth defects, since short stature is a predominant feature in this condition. Underlying mechanisms of STAT3 GOF disease are still poorly understood, and potential effects of STAT3 GOF mutations on the growth hormone signaling pathway are unclear. Functional studies of STAT3 GOF mutations and the broadening of clinical growth-related data in these patients are necessary to better delineate implications of STAT3 GOF mutations on growth.
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Affiliation(s)
- Mariana Gutiérrez
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños R. Gutiérrez, Gallo 1360, Buenos Aires, CP1425EFD, Argentina.
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Strous GJ, Almeida ADS, Putters J, Schantl J, Sedek M, Slotman JA, Nespital T, Hassink GC, Mol JA. Growth Hormone Receptor Regulation in Cancer and Chronic Diseases. Front Endocrinol (Lausanne) 2020; 11:597573. [PMID: 33312162 PMCID: PMC7708378 DOI: 10.3389/fendo.2020.597573] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/14/2020] [Indexed: 12/14/2022] Open
Abstract
The GHR signaling pathway plays important roles in growth, metabolism, cell cycle control, immunity, homeostatic processes, and chemoresistance via both the JAK/STAT and the SRC pathways. Dysregulation of GHR signaling is associated with various diseases and chronic conditions such as acromegaly, cancer, aging, metabolic disease, fibroses, inflammation and autoimmunity. Numerous studies entailing the GHR signaling pathway have been conducted for various cancers. Diverse factors mediate the up- or down-regulation of GHR signaling through post-translational modifications. Of the numerous modifications, ubiquitination and deubiquitination are prominent events. Ubiquitination by E3 ligase attaches ubiquitins to target proteins and induces proteasomal degradation or starts the sequence of events that leads to endocytosis and lysosomal degradation. In this review, we discuss the role of first line effectors that act directly on the GHR at the cell surface including ADAM17, JAK2, SRC family member Lyn, Ubc13/CHIP, proteasome, βTrCP, CK2, STAT5b, and SOCS2. Activity of all, except JAK2, Lyn and STAT5b, counteract GHR signaling. Loss of their function increases the GH-induced signaling in favor of aging and certain chronic diseases, exemplified by increased lung cancer risk in case of a mutation in the SOCS2-GHR interaction site. Insight in their roles in GHR signaling can be applied for cancer and other therapeutic strategies.
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Affiliation(s)
- Ger J. Strous
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
- BIMINI Biotech B.V., Leiden, Netherlands
| | - Ana Da Silva Almeida
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Joyce Putters
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Julia Schantl
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Magdalena Sedek
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Johan A. Slotman
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Tobias Nespital
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Gerco C. Hassink
- Department of Cell Biology, Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Jan A. Mol
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
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Knuth MM, Mahapatra D, Jima D, Wan D, Hammock BD, Law M, Kullman SW. Vitamin D deficiency serves as a precursor to stunted growth and central adiposity in zebrafish. Sci Rep 2020; 10:16032. [PMID: 32994480 PMCID: PMC7524799 DOI: 10.1038/s41598-020-72622-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 09/03/2020] [Indexed: 12/16/2022] Open
Abstract
Emerging evidence demonstrates the importance of sufficient vitamin D (1α, 25-dihydroxyvitamin D3) levels during early life stage development with deficiencies associated with long-term effects into adulthood. While vitamin D has traditionally been associated with mineral ion homeostasis, accumulating evidence suggests non-calcemic roles for vitamin D including metabolic homeostasis. In this study, we examined the hypothesis that vitamin D deficiency (VDD) during early life stage development precedes metabolic disruption. Three dietary cohorts of zebrafish were placed on engineered diets including a standard laboratory control diet, a vitamin D null diet, and a vitamin D enriched diet. Zebrafish grown on a vitamin D null diet between 2-12 months post fertilization (mpf) exhibited diminished somatic growth and enhanced central adiposity associated with accumulation and enlargement of visceral and subcutaneous adipose depots indicative of both adipocyte hypertrophy and hyperplasia. VDD zebrafish exhibited elevated hepatic triglycerides, attenuated plasma free fatty acids and attenuated lipoprotein lipase activity consistent with hallmarks of dyslipidemia. VDD induced dysregulation of gene networks associated with growth hormone and insulin signaling, including induction of suppressor of cytokine signaling. These findings indicate that early developmental VDD impacts metabolic health by disrupting the balance between somatic growth and adipose accumulation.
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Affiliation(s)
- Megan M Knuth
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Campus Box 7633, Raleigh, NC, 27695-7633, USA.
| | - Debabrata Mahapatra
- Comparative Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27606, USA
| | - Dereje Jima
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, 27606, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27606, USA
| | - Debin Wan
- Department of Entomology and Nematology and University of California Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, USA
| | - Bruce D Hammock
- Department of Entomology and Nematology and University of California Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, USA
| | - Mac Law
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27606, USA
| | - Seth W Kullman
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Campus Box 7633, Raleigh, NC, 27695-7633, USA.
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27606, USA.
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Huang S, Liu K, Cheng A, Wang M, Cui M, Huang J, Zhu D, Chen S, Liu M, Zhao X, Wu Y, Yang Q, Zhang S, Ou X, Mao S, Gao Q, Yu Y, Tian B, Liu Y, Zhang L, Yin Z, Jing B, Chen X, Jia R. SOCS Proteins Participate in the Regulation of Innate Immune Response Caused by Viruses. Front Immunol 2020; 11:558341. [PMID: 33072096 PMCID: PMC7544739 DOI: 10.3389/fimmu.2020.558341] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 08/24/2020] [Indexed: 12/17/2022] Open
Abstract
The host immune system has multiple innate immune receptors that can identify, distinguish and react to viral infections. In innate immune response, the host recognizes pathogen-associated molecular patterns (PAMP) in nucleic acids or viral proteins through pathogen recognition receptors (PRRs), especially toll-like receptors (TLRs) and induces immune cells or infected cells to produce type I Interferons (IFN-I) and pro-inflammatory cytokines, thus when the virus invades the host, innate immunity is the earliest immune mechanism. Besides, cytokine-mediated cell communication is necessary for the proper regulation of immune responses. Therefore, the appropriate activation of innate immunity is necessary for the normal life activities of cells. The suppressor of the cytokine signaling proteins (SOCS) family is one of the main regulators of the innate immune response induced by microbial pathogens. They mainly participate in the negative feedback regulation of cytokine signal transduction through Janus kinase signal transducer and transcriptional activator (JAK/STAT) and other signal pathways. Taken together, this paper reviews the SOCS proteins structures and the function of each domain, as well as the latest knowledge of the role of SOCS proteins in innate immune caused by viral infections and the mechanisms by which SOCS proteins assist viruses to escape host innate immunity. Finally, we discuss potential values of these proteins in future targeted therapies.
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Affiliation(s)
- Shanzhi Huang
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ke Liu
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Min Cui
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Juan Huang
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Dekang Zhu
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shun Chen
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mafeng Liu
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xinxin Zhao
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yin Wu
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qiao Yang
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shaqiu Zhang
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xumin Ou
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Sai Mao
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qun Gao
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yanling Yu
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Bin Tian
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yunya Liu
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhang
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhongqiong Yin
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Bo Jing
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaoyue Chen
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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Chung CT, Yeh KC, Lee CH, Chen YY, Ho PJ, Chang KY, Chen CH, Lai YK, Chen CT. Molecular profiling of afatinib-resistant non-small cell lung cancer cells in vivo derived from mice. Pharmacol Res 2020; 161:105183. [PMID: 32896579 DOI: 10.1016/j.phrs.2020.105183] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 08/21/2020] [Accepted: 08/25/2020] [Indexed: 01/28/2023]
Abstract
Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC patients with overexpressed or mutated epidermal growth factor receptor (EGFR) related to disease progression are treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Acquired drug resistance after TKI treatments has been a major focus for development of NSCLC therapies. This study aimed to establish afatinib-resistant cell lines from which afatinib resistance-associated genes are identified and the underlying mechanisms of multiple-TKI resistance in NSCLC can be further investigated. Nude mice bearing subcutaneous NSCLC HCC827 tumors were administered with afatinib at different dose intensities (5-100 mg/kg). We established three HCC827 sublines resistant to afatinib (IC50 > 1 μM) with cross-resistance to gefitinib (IC50 > 5 μM). cDNA microarray revealed several of these sublines shared 27 up- and 13 down-regulated genes. The mRNA expression of selective novel genes - such as transmembrane 4 L six family member 19 (TM4SF19), suppressor of cytokine signaling 2 (SOCS2), and quinolinate phosphoribosyltransferase (QPRT) - are responsive to afatinib treatments only at high concentrations. Furthermore, c-MET amplification and activations of a subset of tyrosine kinase receptors were observed in all three resistant cells. PHA665752, a c-MET inhibitor, remarkably increased the sensitivity of these resistant cells to afatinib (IC50 = 12-123 nM). We established afatinib-resistant lung cancer cell lines and here report genes associated with afatinib resistance in human NSCLC. These cell lines and the identified genes serve as useful investigational tools, prognostic biomarkers of TKI therapies, and promising molecule targets for development of human NSCLC therapeutics.
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Affiliation(s)
- Cheng-Ta Chung
- Graduate Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Kai-Chia Yeh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Chia-Huei Lee
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Yun-Yu Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Pai-Jiun Ho
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Kai-Yen Chang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Chieh-Hsin Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Yiu-Kay Lai
- Graduate Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
| | - Chiung-Tong Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
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Mota de Sá P, Richard AJ, Stephens JM. Bromodomain and Extraterminal Inhibition by JQ1 Produces Divergent Transcriptional Regulation of Suppressors of Cytokine Signaling Genes in Adipocytes. Endocrinology 2020; 161:5686880. [PMID: 31875887 PMCID: PMC7007879 DOI: 10.1210/endocr/bqz034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/18/2019] [Indexed: 12/27/2022]
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway has cell-specific functions. Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of JAK-STAT signaling. STAT5 plays a significant role in adipocyte development and function, and bromodomain and extraterminal (BET) proteins may be involved in STAT5 transcriptional activity. We treated 3T3-L1 adipocytes with the BET inhibitor JQ1 and observed that growth hormone (GH)-induced expression of 2 STAT5 target genes from the SOCS family, Socs3 and Cish, were inversely regulated (increased and decreased, respectively) by BET inhibition. Chromatin immunoprecipitation analyses revealed that changes in STAT5 binding did not correlate with gene expression changes. GH promoted the recruitment of the BET protein BRD2 to the Cish, but not Socs3, promoter. JQ1 treatment ablated this effect as well as the GH-induced binding of ribonucleic acid polymerase II (RNA Pol II) to the Cish transcription start site. BRD2 knockdown also suppressed GH induction of Cish, further supporting the role of BRD2 in Cish transcriptional activation. In contrast, JQ1 increased the binding of activated Pol II to the Socs3 coding region, suggesting enhanced messenger RNA (mRNA) elongation. Our finding that JQ1 transiently reduced the interaction between the positive transcription elongation factor (P-TEFb) and its inhibitor hexamethylene bis-acetamide inducible 1 (HEXIM1) is consistent with a previously described off-target effect of JQ1, whereby P-TEFb becomes more available to be recruited by genes that do not depend on BET proteins for activating transcription. These results demonstrate substantially different transcriptional regulation of Socs3 and Cish and suggest distinct roles in adipocytes for these 2 closely related proteins.
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Affiliation(s)
- Paula Mota de Sá
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana
| | - Allison J Richard
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana
| | - Jacqueline M Stephens
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana
- Correspondence: Jacqueline Stephens, Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70803. E-mail:
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Wu X, Cai D, Zhang F, Li M, Wan Q. Long noncoding RNA TUSC7 inhibits cell proliferation, migration and invasion by regulating SOCS4 (SOCS5) expression through targeting miR-616 in endometrial carcinoma. Life Sci 2019; 231:116549. [PMID: 31200002 DOI: 10.1016/j.lfs.2019.116549] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 06/04/2019] [Accepted: 06/07/2019] [Indexed: 02/09/2023]
Abstract
BACKGROUND Long non-coding RNA (lncRNA) is emerging as an important regulator in various physiological and pathological processes. Recently, it was found that lncRNA long non-coding RNA tumor suppressor candidate 7 (TUSC7) could play tumor suppressive roles in several cancers. However, the function and underlying regulatory mechanism of lncRNA TUSC7 in endometrial carcinoma (EC) remains largely unclear. METHODS The expression levels of TUSC7 and microRNAs-616 (miR-616) were analyzed by real-time PCR and in situ hybridization. Cell cycle and cell metastasis associated protein expressions were determined by western blotting. Cell proliferation, cycle and metastasis were determined by CCK-8 cell viability, colony formation, flow cytometer, wound scratch and transwell assays respectively in vitro. RNA pull-down, luciferase and western blotting assays were used to examine the target relationship between TUSC7 and miR-616 or that between miR-616 and suppressors of cytokine signaling 4 (5) (SOCS4 (SOCS5)). The functional effects of TUSC7 through sponging miR-616 were further examined using a xenograft tumor mouse model in vivo. RESULTS TUSC7 was downexpressed in EC tissues and cell lines, and TUSC7 upregulation could remarkably inhibit cell proliferation, cycle progression and metastasis in EC cells. Mechanistic investigations demonstrated that TUSC7 can interact with miR-616 and decrease its expression, thereby upregulating the expression of miR-616's targets SOCS4 (SOCS5). Additionally, in vivo experiments using a xenograft tumor mouse model revealed that TUSC7 can serve as a tumor suppressor through sponging miR-616, and upregulating SOCS4 (SOCS5) in EC. CONCLUSIONS In this study, a newly identified regulatory mechanism of lncRNA TUSC7/miR-616/ SOCS4 (SOCS5) axis was systematically studied, which may hold promise as a promising target for EC treatment.
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Affiliation(s)
- Xiaoling Wu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Dongge Cai
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Fan Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Mu Li
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Qiuyuan Wan
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
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Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase. Nat Commun 2019; 10:2534. [PMID: 31182716 PMCID: PMC6557900 DOI: 10.1038/s41467-019-10190-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 04/26/2019] [Indexed: 01/10/2023] Open
Abstract
The suppressor of cytokine signaling 2 (SOCS2) acts as substrate recognition subunit of a Cullin5 E3 ubiquitin ligase complex. SOCS2 binds to phosphotyrosine-modified epitopes as degrons for ubiquitination and proteasomal degradation, yet the molecular basis of substrate recognition has remained elusive. Here, we report co-crystal structures of SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from substrates growth hormone receptor (GHR-pY595) and erythropoietin receptor (EpoR-pY426) at 1.98 Å and 2.69 Å, respectively. Both peptides bind in an extended conformation recapitulating the canonical SH2 domain-pY pose, but capture different conformations of the EF loop via specific hydrophobic interactions. The flexible BG loop is fully defined in the electron density, and does not contact the substrate degron directly. Cancer-associated SNPs located around the pY pocket weaken substrate-binding affinity in biophysical assays. Our findings reveal insights into substrate recognition and specificity by SOCS2, and provide a blueprint for small molecule ligand design. The suppressor of cytokine signaling 2 (SOCS2) is a component of the Cullin5 E3 ubiquitin ligase complex. Here the authors provide insights into substrate recognition and specificity of SOCS2 by determining the crystal structures of the SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from two of its substrates the growth hormone receptor and erythropoietin receptor.
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40
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SOCS1 and its Potential Clinical Role in Tumor. Pathol Oncol Res 2019; 25:1295-1301. [DOI: 10.1007/s12253-019-00612-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/04/2019] [Indexed: 10/27/2022]
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Takeshima H, Horie M, Mikami Y, Makita K, Miyashita N, Matsuzaki H, Noguchi S, Urushiyama H, Hiraishi Y, Mitani A, Borok Z, Nagase T, Yamauchi Y. CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts. Allergol Int 2019; 68:101-109. [PMID: 30197185 DOI: 10.1016/j.alit.2018.08.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/02/2018] [Accepted: 08/05/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts. METHODS Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively. RESULTS Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/β signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26. CONCLUSIONS These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma.
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Fink J, Matsumoto M, Tamura Y. Potential application of testosterone replacement therapy as treatment for obesity and type 2 diabetes in men. Steroids 2018; 138:161-166. [PMID: 30118780 DOI: 10.1016/j.steroids.2018.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 07/24/2018] [Accepted: 08/03/2018] [Indexed: 01/04/2023]
Abstract
Sedentary lifestyle and over-nutrition are the main causes of obesity and type 2 diabetes (T2D). However, the same causes are major triggers of hypogonadism. Many T2D patients show low testosterone levels while hypogonadal men seem to be prone to become diabetic. Testosterone plays a major role in the regulation of muscle mass, adipose tissue, inflammation and insulin sensitivity and is therefore indirectly regulating several metabolic pathways, while T2D is commonly triggered by insulin resistance, increased adipose tissue and inflammation, showing a negative correlation between testosterone levels and T2D. Testosterone replacement therapy (TRT) is widely used in patients with symptoms of hypogonadism, however it is not commonly used as preventive intervention or treatment for T2D patients even though hypogonadal patients share many common symptoms (obesity, insulin insensitivity, increased inflammation, decrease in muscle mass and strength) with T2D patients. Even though TRT is often associated with side effects such as prostatic hypertrophy or cancer, cardiovascular risks due to increase in the number of red blood cells and infertility, several studies have shown that TRT remains a potent intervention improving metabolic functions such as glycated haemoglobin, blood sugar, total cholesterol and visceral fat. The purpose of this review is to discuss the possible benefits and risks of TRT in the prevention and treatment of obesity and T2D and assess the health risks and benefits of common T2D medications and testosterone.
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Affiliation(s)
- Julius Fink
- Graduate School of Medicine, Department of Metabolism and Endocrinology, Juntendo University, Tokyo, Japan.
| | - Masahito Matsumoto
- Graduate School of Medicine, Department of Metabolism and Endocrinology, Juntendo University, Tokyo, Japan; Advanced Diabetic Therapeutics, Department of Metabolic Endocrinology, Juntendo University, Tokyo, Japan
| | - Yoshifumi Tamura
- Graduate School of Medicine, Department of Metabolism and Endocrinology, Juntendo University, Tokyo, Japan
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Wójcik M, Krawczyńska A, Antushevich H, Herman AP. Post-Receptor Inhibitors of the GHR-JAK2-STAT Pathway in the Growth Hormone Signal Transduction. Int J Mol Sci 2018; 19:E1843. [PMID: 29932147 PMCID: PMC6073700 DOI: 10.3390/ijms19071843] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/15/2018] [Accepted: 06/19/2018] [Indexed: 02/06/2023] Open
Abstract
The growth hormone (GH) plays a key role in the regulation of metabolic processes in an organism. Determination of the correct structure and functioning of the growth hormone receptor (GHR) allowed for a more detailed research of its post-receptor regulators, which substantially influences its signal transduction. This review is focused on the description of the post-receptor inhibitors of the GHR-JAK2-STAT pathway, which is one of the most important pathways in the transduction of the somatotropic axis signal. The aim of this review is the short characterization of the main post-receptor inhibitors, such as: cytokine-inducible SH2-containing protein (CIS), Suppressors of Cytokine Signaling (SOCS) 1, 2 and 3, sirtuin 1 (SIRT1), protein inhibitors of activated STAT (PIAS) 1, 3 and PIAS4, protein tyrosine phosphatases (PTP) 1B and H1, Src homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP) 1, 2 and signal regulatory protein (SIRP) α1. The equilibrium between these regulators activity and inhibition is of special concern because, as many studies showed, even slight imbalance may disrupt the GH activity causing serious diseases. The regulation of the described inhibitors expression and activity may be a point of interest for pharmaceutical industry.
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Affiliation(s)
- Maciej Wójcik
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, ul. Instytucka 3, 05-110 Jabłonna, Poland.
| | - Agata Krawczyńska
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, ul. Instytucka 3, 05-110 Jabłonna, Poland.
| | - Hanna Antushevich
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, ul. Instytucka 3, 05-110 Jabłonna, Poland.
| | - Andrzej Przemysław Herman
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, ul. Instytucka 3, 05-110 Jabłonna, Poland.
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Cui T, Schally AV. Growth hormone-releasing hormone (GHRH) and its agonists inhibit hepatic and tumoral secretion of IGF-1. Oncotarget 2018; 9:28745-28756. [PMID: 29983893 PMCID: PMC6033336 DOI: 10.18632/oncotarget.25676] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 06/12/2018] [Indexed: 12/16/2022] Open
Abstract
The role of hypothalamic growth hormone-releasing hormone (GHRH) in the release of growth hormone (GH) from the pituitary is well established. However, direct effects of GHRH and its agonistic analogs on extra-pituitary cells and tissues have not been completely elucidated. In the present study, we first demonstrated that human and rat hepatocytes express receptors for GHRH. We then showed that GHRH(1-29)NH 2 and GHRH agonist, MR-409, downregulated mRNA levels for IGF-1 in human cancer cell lines and inhibited IGF-1 secretion in vitro when these cancer lines were exposed to rhGH. Another GHRH agonist, MR-356, lowered serum IGF-l and inhibited tumor growth in nude mice bearing xenografted NCI-N87 human stomach cancers. GHRH(1-29)NH 2 and MR-409 also suppressed the expression of mRNA for IGF-1 and IGF-2 in rat and human hepatocytes, decreased the secretion of IGF-1 in vitro from rat hepatocytes stimulated with rhGH, and lowered serum IGF-l levels in hypophysectomized rats injected with rhGH. Vasoactive intestinal peptide had no effect on the release of IGF-1 from the hepatocytes. Treatment of C57BL/6 mice with MR-409 reduced serum levels of IGF-l from days 1 to 5. These results show that GHRH and its agonists can, by a direct action, inhibit the secretion of IGF-1 from the liver and from tumors. The inhibitory effect of GHRH appears to be mediated by the GHRH receptor (GHRH-R) and GH receptor (GHR), with the involvement of JAK2/STAT5 pathways. Further studies are required to investigate the possible physiopathological role of GHRH in the control of secretion of IGF-1.
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Affiliation(s)
- Tengjiao Cui
- Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA
- Department of Medicine, Divisions of Hematology, Oncology and Endocrinology, University of Miami, Miami, FL, USA
| | - Andrew V. Schally
- Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA
- Department of Medicine, Divisions of Hematology, Oncology and Endocrinology, University of Miami, Miami, FL, USA
- Department of Pathology, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
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Naudin C, Chevalier C, Roche S. The role of small adaptor proteins in the control of oncogenic signalingr driven by tyrosine kinases in human cancer. Oncotarget 2017; 7:11033-55. [PMID: 26788993 PMCID: PMC4905456 DOI: 10.18632/oncotarget.6929] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 01/01/2016] [Indexed: 12/15/2022] Open
Abstract
Protein phosphorylation on tyrosine (Tyr) residues has evolved as an important mechanism to coordinate cell communication in multicellular organisms. The importance of this process has been revealed by the discovery of the prominent oncogenic properties of tyrosine kinases (TK) upon deregulation of their physiological activities, often due to protein overexpression and/or somatic mutation. Recent reports suggest that TK oncogenic signaling is also under the control of small adaptor proteins. These cytosolic proteins lack intrinsic catalytic activity and signal by linking two functional members of a catalytic pathway. While most adaptors display positive regulatory functions, a small group of this family exerts negative regulatory functions by targeting several components of the TK signaling cascade. Here, we review how these less studied adaptor proteins negatively control TK activities and how their loss of function induces abnormal TK signaling, promoting tumor formation. We also discuss the therapeutic consequences of this novel regulatory mechanism in human oncology.
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Affiliation(s)
- Cécile Naudin
- CNRS UMR5237, University Montpellier, CRBM, Montpellier, France.,Present address: INSERM U1016, CNRS UMR8104, Institut Cochin, Paris, France
| | - Clément Chevalier
- CNRS UMR5237, University Montpellier, CRBM, Montpellier, France.,Present address: SFR Biosit (UMS CNRS 3480/US INSERM 018), MRic Photonics Platform, University Rennes, Rennes, France
| | - Serge Roche
- CNRS UMR5237, University Montpellier, CRBM, Montpellier, France.,Equipe Labellisée LIGUE 2014, Ligue Contre le Cancer, Paris, France
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Heppler LN, Frank DA. Targeting Oncogenic Transcription Factors: Therapeutic Implications of Endogenous STAT Inhibitors. Trends Cancer 2017; 3:816-827. [PMID: 29198438 DOI: 10.1016/j.trecan.2017.10.004] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/10/2017] [Accepted: 10/11/2017] [Indexed: 02/07/2023]
Abstract
Misregulation of transcription factors, including signal transducer and activator of transcription (STAT) proteins, leads to inappropriate gene expression patterns that can promote tumor initiation and progression. Under physiologic conditions, STAT signaling is stimulus dependent and tightly regulated by endogenous inhibitors, namely, suppressor of cytokine signaling (SOCS) proteins, phosphatases, and protein inhibitor of activated STAT (PIAS) proteins. However, in tumorigenesis, STAT proteins become constitutively active and promote the expression of progrowth and prosurvival genes. Although STAT activation has been widely implicated in cancer, therapeutic STAT inhibitors are still largely absent from the clinic. This review dissects the mechanisms of action of two families of endogenous STAT inhibitors, the SOCS and PIAS families, to potentially inform the development of novel therapeutic inhibitors.
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Affiliation(s)
- Lisa N Heppler
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - David A Frank
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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Cianciulli A, Calvello R, Porro C, Trotta T, Panaro MA. Understanding the role of SOCS signaling in neurodegenerative diseases: Current and emerging concepts. Cytokine Growth Factor Rev 2017; 37:67-79. [DOI: 10.1016/j.cytogfr.2017.07.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 07/28/2017] [Accepted: 07/29/2017] [Indexed: 12/15/2022]
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Kim SH, Park MJ. Effects of growth hormone on glucose metabolism and insulin resistance in human. Ann Pediatr Endocrinol Metab 2017; 22:145-152. [PMID: 29025199 PMCID: PMC5642081 DOI: 10.6065/apem.2017.22.3.145] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 09/11/2017] [Indexed: 01/02/2023] Open
Abstract
Growth hormone (GH) is important for promotion of somatic growth and the regulation of substrate metabolism. Metabolic action of GH occurs in multiple tissues including the liver, muscle, fat and pancreas either directly or indirectly through insulin-like growth factor 1. The diabetogenic action of GH has been well-described in previous in vivo studies. In this paper, we review the metabolic effects of GH on peripheral tissues focusing on glucose metabolism and insulin resistance, and discuss results from human studies on the long-term effects of GH administration on insulin resistance and hyperglycemia.
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Affiliation(s)
| | - Mi-Jung Park
- Address for correspondence: Mi-Jung Park, MD, PhD http://orcid.org/0000-0002-7202-500X Department of Pediatrics, Inje University Sanggye Paik Hospital, 1342 Dongilro, Nowon-gu, Seoul 01767, Korea Tel: +82-2-950-8826 Fax: +82-2-950-1246 E-mail:
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Li L, Lei QS, Kong LN, Zhang SJ, Qin B. Gene expression profile after knockdown of USP18 in Hepg2.2.15 cells. J Med Virol 2017; 89:1920-1930. [PMID: 28369997 DOI: 10.1002/jmv.24819] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 03/13/2017] [Indexed: 01/18/2023]
Abstract
In our previous work, we found that the expression of ubiquitin-specific protease 18 (USP18), also known as UBP43, is associated with the efficiency of interferon alpha (IFN-α) treatment in patients with chronic hepatitis B (CHB). To elucidate the influence of USP18 on hepatitis B virus (HBV) replication and the mechanism of this activity, we silenced USP18 by introducing short hairpin RNA (shRNA) into Hepg2.2.15 cells. To identify the changed genes and pathways in Hepg2.2.15-shRNA-USP18 cells, we performed a microarray gene expression analysis to compare the Hepg2.2.15 stably expressing USP18-shRNA cells versus control cells using the Affymetrix Human Transcriptome Array (HTA) 2.0 microarrays. Microarray analysis indicated that genes involved in regulation of thyroid hormone signaling pathway, complement, and coagulation cascades, PERK-mediated unfolded protein response, and insulin-like growth factor-activated receptor activity were significantly altered after USP18 knockdown for 72 h. Furthermore, genes involved in hepatocyte proliferation, liver fibrosis, such as cell cycle regulatory gene CCND1, were also altered after USP18 knockdown in Hepg2.2.15 cells. In conclusion, USP18 is critical for regulating the replication of HBV in Hepg2.2.15 cells, which suggest that USP18 may be a candidate target for HBV treatment.
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Affiliation(s)
- Lin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing-Song Lei
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ling-Na Kong
- School of Nursing, Chongqing Medical University, Chongqing, China
| | - Shu-Jun Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Qin
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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50
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Xiong H, Zhang Y, Chen S, Ni Z, He J, Li X, Li B, Zhao K, Yang F, Zeng Y, Chen B, He F. Induction of SOCS3 by liver X receptor suppresses the proliferation of hepatocellular carcinoma cells. Oncotarget 2017; 8:64083-64094. [PMID: 28969053 PMCID: PMC5609985 DOI: 10.18632/oncotarget.19321] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 06/10/2017] [Indexed: 02/06/2023] Open
Abstract
Liver X receptor (LXR), a member of nuclear receptor superfamily, is involved in the regulation of glucose, lipid and cholesterol metabolism. Recently, it has been reported that LXR suppress different kinds of cancers including hepatocellular carcinoma (HCC). However, the corresponding mechanism is still not well elucidated. In the present study, we found that activation of LXR downregulated cyclin D1 while upregulated p21 and p27 by elevating the level of suppressor of cytokine signaling 3 (SOCS3), leading to the cell cycle arrest at G1/S phase and growth inhibition of HCC cells. Moreover, we demonstrated that LXRα (not LXRβ) mediated the induction of SOCS3 in HCC cells. Subsequently, we showed that LXR activation enhanced the mRNA stability of SOCS3, but had no significant influence on the transcriptional activity of SOCS3 gene promoter. The experiments in nude mice revealed that LXR agonist inhibited the growth of xenograft tumors and enhanced SOCS3 expression in vivo. These results indicate that “LXRα-SOCS3-cyclin D1/p21/p27” is a novel pathway by which LXR exerts its anti-HCC effects, suggesting that the pathway may be a new potential therapeutic target for HCC treatment.
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Affiliation(s)
- Haojun Xiong
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yan Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Shan Chen
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Zhenhong Ni
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Jintao He
- Battalion 17 of Students, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China
| | - Xinzhe Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Bo Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Kai Zhao
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Fan Yang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yijun Zeng
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Bingbo Chen
- Laboratory Animal Center, Third Military Medical University, Chongqing 400038, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
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