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Cui X, Song Y, Han J, Yuan Z. The multifaceted role of SMAD4 in immune cell function. Biochem Biophys Rep 2025; 41:101902. [PMID: 39802394 PMCID: PMC11721226 DOI: 10.1016/j.bbrep.2024.101902] [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: 08/30/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.
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Affiliation(s)
- Xinmu Cui
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Yu Song
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Jianfeng Han
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
- Cellular Biomedicine Group Inc, Shanghai, 201203, China
| | - Zhaoxin Yuan
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
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Ali S, Rehman MU, Yatoo AM, Arafah A, Khan A, Rashid S, Majid S, Ali A, Ali MN. TGF-β signaling pathway: Therapeutic targeting and potential for anti-cancer immunity. Eur J Pharmacol 2023; 947:175678. [PMID: 36990262 DOI: 10.1016/j.ejphar.2023.175678] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 03/07/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023]
Abstract
Transforming growth factor-β (TGFβ) is a pleiotropic secretory cytokine exhibiting both cancer-inhibitory and promoting properties. It transmits its signals via Suppressor of Mother against Decapentaplegic (SMAD) and non-SMAD pathways and regulates cell proliferation, differentiation, invasion, migration, and apoptosis. In non-cancer and early-stage cancer cells, TGFβ signaling suppresses cancer progression via inducing apoptosis, cell cycle arrest, or anti-proliferation, and promoting cell differentiation. On the other hand, TGFβ may also act as an oncogene in advanced stages of tumors, wherein it develops immune-suppressive tumor microenvironments and induces the proliferation of cancer cells, invasion, angiogenesis, tumorigenesis, and metastasis. Higher TGFβ expression leads to the instigation and development of cancer. Therefore, suppressing TGFβ signals may present a potential treatment option for inhibiting tumorigenesis and metastasis. Different inhibitory molecules, including ligand traps, anti-sense oligo-nucleotides, small molecule receptor-kinase inhibitors, small molecule inhibitors, and vaccines, have been developed and clinically trialed for blocking the TGFβ signaling pathway. These molecules are not pro-oncogenic response-specific but block all signaling effects induced by TGFβ. Nonetheless, targeting the activation of TGFβ signaling with maximized specificity and minimized toxicity can enhance the efficacy of therapeutic approaches against this signaling pathway. The molecules that are used to target TGFβ are non-cytotoxic to cancer cells but designed to curtail the over-activation of invasion and metastasis driving TGFβ signaling in stromal and cancer cells. Here, we discussed the critical role of TGFβ in tumorigenesis, and metastasis, as well as the outcome and the promising achievement of TGFβ inhibitory molecules in the treatment of cancer.
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3
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Zhao S, Zhang X, Chen S, Zhang S. Long noncoding RNAs: fine-tuners hidden in the cancer signaling network. Cell Death Dis 2021; 7:283. [PMID: 34635646 PMCID: PMC8505617 DOI: 10.1038/s41420-021-00678-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 09/04/2021] [Accepted: 09/27/2021] [Indexed: 02/08/2023]
Abstract
With the development of sequencing technology, a large number of long non-coding RNAs (lncRNAs) have been identified in addition to coding genes. LncRNAs, originally considered as junk RNA, are dysregulated in various types of cancer. Although protein-coding signaling pathways underlie various biological activities, and abnormal signal transduction is a key trigger and indicator for tumorigenesis and cancer progression, lncRNAs are sparking keen interest due to their versatile roles in fine-tuning signaling pathways. We are just beginning to scratch the surface of lncRNAs. Therefore, despite the fact that lncRNAs drive malignant phenotypes from multiple perspectives, in this review, we focus on important signaling pathways modulated by lncRNAs in cancer to demonstrate an up-to-date understanding of this emerging field.
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Affiliation(s)
- Shanshan Zhao
- grid.412467.20000 0004 1806 3501Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Reproductive Medicine Center, Obstetrics and Gynecology Department, Shengjing Hospital Affiliated to China Medical University, 110022 Shenyang, Liaoning China
| | - Xue Zhang
- grid.412449.e0000 0000 9678 1884Department of Epigenetics, China Medical University, 110122 Shenyang, Liaoning China
| | - Shuo Chen
- grid.417009.b0000 0004 1758 4591Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, 510150 Guangzhou, Guangdong China
| | - Song Zhang
- grid.412636.4Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, 110001 Shenyang, Liaoning China ,grid.412449.e0000 0000 9678 1884Department of Environmental and Occupational Health, School of Public Health, China Medical University, 110122 Shenyang, Liaoning China
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4
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Li FJ, Surolia R, Li H, Wang Z, Liu G, Kulkarni T, Massicano AVF, Mobley JA, Mondal S, de Andrade JA, Coonrod SA, Thompson PR, Wille K, Lapi SE, Athar M, Thannickal VJ, Carter AB, Antony VB. Citrullinated vimentin mediates development and progression of lung fibrosis. Sci Transl Med 2021; 13:13/585/eaba2927. [PMID: 33731433 DOI: 10.1126/scitranslmed.aba2927] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/06/2020] [Accepted: 10/26/2020] [Indexed: 12/12/2022]
Abstract
The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)-dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-β1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not PAD2-/- and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.
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Affiliation(s)
- Fu Jun Li
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ranu Surolia
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Huashi Li
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Zheng Wang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Gang Liu
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Tejaswini Kulkarni
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Adriana V F Massicano
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - James A Mobley
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Santanu Mondal
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Joao A de Andrade
- Vanderbilt Lung Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA
| | - Scott A Coonrod
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Paul R Thompson
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Keith Wille
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Suzanne E Lapi
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Mohammad Athar
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Victor J Thannickal
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Birmingham VA Medical Center, Birmingham, AL 35294, USA
| | - A Brent Carter
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Birmingham VA Medical Center, Birmingham, AL 35294, USA
| | - Veena B Antony
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Yao J, Lin C, Jiang J, Zhang X, Li F, Liu T, Diao H. lncRNA-HEIM Facilitated Liver Fibrosis by Up-Regulating TGF- β Expression in Long-Term Outcome of Chronic Hepatitis B. Front Immunol 2021; 12:666370. [PMID: 34168644 PMCID: PMC8217658 DOI: 10.3389/fimmu.2021.666370] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/18/2021] [Indexed: 12/26/2022] Open
Abstract
Background Chronic liver fibrosis is an inevitable stage for the development of patients with chronic hepatitis B (CHB). However, anti-fibrotic therapies have been unsuccessful so far. The biological functions and molecular mechanisms of long non-coding RNAs (lncRNAs) in the host immune system during chronic hepatitis B virus (HBV) infection, especially in fibrosis, are still largely unknown. Method The total RNA of peripheral blood mononuclear cells (PBMCs) from asymptomatic carriers (ASCs) or CHB receiving at least 8 years of anti-viral treatments was analyzed using Arraystar microarray and validated via quantitative real-time PCR (qRT-PCR). Correlation analysis was conducted based on correlation coefficients, Clusterprofile, and RNA Interactome Database (RAID). The functions of lncRNA in monocytes were determined via loss-of-function RNAi or gain-of-function lentivirus assays. The expression levels of mRNAs or proteins were evaluated using qRT-PCR, western blotting assay, or enzyme linked immunosorbent assays (ELISA). Results A total of 1,042 mRNA transcripts (630 up-regulated and 412 down-regulated) were identified being differentially expressed between ASC and CHB patients. Through enrichment analysis we focused on the transforming growth factor beta (TGF-β) signaling pathway and validated their expression in a larger cohort. Moreover, we found that lncRNA ENST00000519726 (lncRNA-HEIM) was highly expressed in monocytes and further up-regulated upon HBV infection. LncRNA-HEIM played an important role in CHB patients with long-term antiviral treatments, and its elevated expression was remarkably correlated with the TGF-β signaling pathway, especially with the two members namely TGF-β and SMAD4. Furthermore, altering the endogenous lncRNA-HEIM level in monocytes significantly affected the production of TGF-β, as well as the fibrosis of hepatic stellate cells by affecting the expression of collagen I and α-smooth muscle actin (α-SMA). Conclusion These findings not only added knowledge to the understanding of the roles of which lncRNA-HEIM played in the activation of HSCs in CHB patients with long-term medication, but also provided a promising therapeutic target in the future treatment for liver fibrosis.
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Affiliation(s)
- Jian Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Chenhong Lin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jingjing Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xujun Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Fengxia Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Tianxing Liu
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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6
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Kamato D, Little PJ. Smad2 linker region phosphorylation is an autonomous cell signalling pathway: Implications for multiple disease pathologies. Biomed Pharmacother 2020; 124:109854. [DOI: 10.1016/j.biopha.2020.109854] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/13/2020] [Accepted: 01/16/2020] [Indexed: 12/18/2022] Open
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7
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Herdy J, Schafer S, Kim Y, Ansari Z, Zangwill D, Ku M, Paquola A, Lee H, Mertens J, Gage FH. Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons. eLife 2019; 8:e41356. [PMID: 31099332 PMCID: PMC6524968 DOI: 10.7554/elife.41356] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 05/01/2019] [Indexed: 12/22/2022] Open
Abstract
Direct conversion of human somatic fibroblasts into induced neurons (iNs) allows for the generation of functional neurons while bypassing any stem cell intermediary stages. Although iN technology has an enormous potential for modeling age-related diseases, as well as therapeutic approaches, the technology faces limitations due to variable conversion efficiencies and a lack of thorough understanding of the signaling pathways directing iN conversion. Here, we introduce a new all-in-one inducible lentiviral system that simplifies fibroblast transgenesis for the two pioneer transcription factors, Ngn2 and Ascl1, and markedly improves iN yields. Further, our timeline RNA-Seq data across the course of conversion has identified signaling pathways that become transcriptionally enriched during iN conversion. Small molecular modulators were identified for four signaling pathways that reliably increase the yield of iNs. Taken together, these advances provide an improved toolkit for iN technology and new insight into the mechanisms influencing direct iN conversion.
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Affiliation(s)
- Joseph Herdy
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
| | - Simon Schafer
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
| | - Yongsung Kim
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
| | - Zoya Ansari
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
| | - Dina Zangwill
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
| | - Manching Ku
- University Hospital Freiberg, University of FreibergBreisgauGermany
| | - Apua Paquola
- Lieber Institute for Brain DevelopmentBaltimoreUnited States
| | - Hyungjun Lee
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
| | - Jerome Mertens
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
- Institute of Molecular Biology, CMBILeopold-Franzens-University InnsbruckInnsbruckAustria
| | - Fred H Gage
- Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUnited States
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Hao Y, Bjerke GA, Pietrzak K, Melhuish TA, Han Y, Turner SD, Frierson HF, Wotton D. TGFβ signaling limits lineage plasticity in prostate cancer. PLoS Genet 2018; 14:e1007409. [PMID: 29782499 PMCID: PMC5983872 DOI: 10.1371/journal.pgen.1007409] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 06/01/2018] [Accepted: 05/10/2018] [Indexed: 01/08/2023] Open
Abstract
Although treatment options for localized prostate cancer (CaP) are initially effective, the five-year survival for metastatic CaP is below 30%. Mutation or deletion of the PTEN tumor suppressor is a frequent event in metastatic CaP, and inactivation of the transforming growth factor (TGF) ß signaling pathway is associated with more advanced disease. We previously demonstrated that mouse models of CaP based on inactivation of Pten and the TGFß type II receptor (Tgfbr2) rapidly become invasive and metastatic. Here we show that mouse prostate tumors lacking Pten and Tgfbr2 have higher expression of stem cell markers and genes indicative of basal epithelial cells, and that basal cell proliferation is increased compared to Pten mutants. To better model the primarily luminal phenotype of human CaP we mutated Pten and Tgfbr2 specifically in luminal cells, and found that these tumors also progress to invasive and metastatic cancer. Accompanying the transition to invasive cancer we observed de-differentiation of luminal tumor cells to an intermediate cell type with both basal and luminal markers, as well as differentiation to basal cells. Proliferation rates in these de-differentiated cells were lower than in either basal or luminal cells. However, de-differentiated cells account for the majority of cells in micro-metastases consistent with a preferential contribution to metastasis. We suggest that active TGFß signaling limits lineage plasticity in prostate luminal cells, and that de-differentiation of luminal tumor cells can drive progression to metastatic disease.
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Affiliation(s)
- Yi Hao
- Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, United States of America
| | - Glen A. Bjerke
- Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, United States of America
| | - Karolina Pietrzak
- Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, United States of America
- Department of Cytobiochemistry, University of Lodz, Lodz, Poland
| | - Tiffany A. Melhuish
- Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, United States of America
| | - Yu Han
- Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, United States of America
| | - Stephen D. Turner
- Department of Public Health Sciences, University of Virginia, Charlottesville, United States of America
| | - Henry F. Frierson
- Department of Pathology, University of Virginia, Charlottesville, United States of America
| | - David Wotton
- Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, United States of America
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Xiong S, Cheng JC, Klausen C, Zhao J, Leung PCK. TGF-β1 stimulates migration of type II endometrial cancer cells by down-regulating PTEN via activation of SMAD and ERK1/2 signaling pathways. Oncotarget 2018; 7:61262-61272. [PMID: 27542208 PMCID: PMC5308649 DOI: 10.18632/oncotarget.11311] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 08/10/2016] [Indexed: 11/25/2022] Open
Abstract
PTEN acts as a tumor suppressor primarily by antagonizing the PI3K/AKT signaling pathway. PTEN is frequently mutated in human cancers; however, in type II endometrial cancers its mutation rate is very low. Overexpression of TGF-β1 and its receptors has been reported to correlate with metastasis of human cancers and reduced survival rates. Although TGF-β1 has been shown to regulate PTEN expression through various mechanisms, it is not yet known if the same is true in type II endometrial cancer. In the present study, we show that treatment with TGF-β1 stimulates the migration of two type II endometrial cancer cell lines, KLE and HEC-50. In addition, TGF-β1 treatment down-regulates both mRNA and protein levels of PTEN. Overexpression of PTEN or inhibition of PI3K abolishes TGF-β1-stimulated cell migration. TGF-β1 induces SMAD2/3 phosphorylation and knockdown of common SMAD4 inhibits the suppressive effects of TGF-β1 on PTEN mRNA and protein. Interestingly, TGF-β1 induces ERK1/2 phosphorylation and pre-treatment with a MEK inhibitor attenuates the suppression of PTEN protein, but not mRNA, by TGF-β1. This study provides important insights into the molecular mechanisms mediating TGF-β1-induced down-regulation of PTEN and demonstrates an important role of PTEN in the regulation of type II endometrial cancer cell migration.
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Affiliation(s)
- Siyuan Xiong
- Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
| | - Jung-Chien Cheng
- Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
| | - Christian Klausen
- Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
| | - Jianfang Zhao
- Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
| | - Peter C K Leung
- Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
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10
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Hsu WL, Ma YL, Liu YC, Lee EHY. Smad4 SUMOylation is essential for memory formation through upregulation of the skeletal myopathy gene TPM2. BMC Biol 2017; 15:112. [PMID: 29183317 PMCID: PMC5706330 DOI: 10.1186/s12915-017-0452-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Accepted: 11/07/2017] [Indexed: 11/22/2022] Open
Abstract
Background Smad4 is a critical effector of TGF-β signaling that regulates a variety of cellular functions. However, its role in the brain has rarely been studied. Here, we examined the molecular mechanisms underlying the post-translational regulation of Smad4 function by SUMOylation, and its role in spatial memory formation. Results In the hippocampus, Smad4 is SUMOylated by the E3 ligase PIAS1 at Lys-113 and Lys-159. Both spatial training and NMDA injection enhanced Smad4 SUMOylation. Inhibition of Smad4 SUMOylation impaired spatial learning and memory in rats by downregulating TPM2, a gene associated with skeletal myopathies. Similarly, knockdown of TPM2 expression impaired spatial learning and memory, while TPM2 mRNA and protein expression increased after spatial training. Among the TPM2 mutations associated with skeletal myopathies, the TPM2E122K mutation was found to reduce TPM2 expression and impair spatial learning and memory in rats. Conclusions We have identified a novel role of Smad4 SUMOylation and TPM2 in learning and memory formation. These results suggest that patients with skeletal myopathies who carry the TPM2E122K mutation may also have deficits in learning and memory functions. Electronic supplementary material The online version of this article (doi:10.1186/s12915-017-0452-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei L Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Yun L Ma
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Yen C Liu
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Eminy H Y Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. .,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.
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11
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Yuan T, Chen Y, Zhang H, Fang L, Du G. Salvianolic Acid A, a Component of Salvia miltiorrhiza, Attenuates Endothelial-Mesenchymal Transition of HPAECs Induced by Hypoxia. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:1185-1200. [PMID: 28893092 DOI: 10.1142/s0192415x17500653] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Salvianolic acid A (SAA), a polyphenols acid, is a bioactive ingredient from a traditional Chinese medicine called Dan shen (Salvia Miltiorrhiza Bunge). According to previous studies, it was shown to have various effects such as anti-oxidative stress, antidiabetic complications and antipulmonary hypertension. This study aimed to investigate the effect of SAA on pulmonary arterial endothelial-mesenchymal transition (EndoMT) induced by hypoxia and the underlying mechanisms. Primary cultured human pulmonary arterial endothelial cells (HPAECs) were exposed to 1% O2 for 48[Formula: see text]h with or without SAA treatment. SAA treatment improved the morphology of HPAECs and inhibited the cytoskeleton remodeling. A total of 3[Formula: see text][Formula: see text]M SAA reduced migration distances from 262.2[Formula: see text][Formula: see text]m to 198.4[Formula: see text][Formula: see text]m at 24[Formula: see text]h and 344.8[Formula: see text][Formula: see text]m to 109.3[Formula: see text][Formula: see text]m at 48[Formula: see text]h. It was observed that the production of ROS in cells was significantly reduced by the treatment of 3[Formula: see text][Formula: see text]M SAA. Meanwhile, SAA alleviated the loss of CD31 and slightly inhibited the expression of [Formula: see text]-SMA. The mechanisms study shows that SAA treatment increased the phosphorylation levels of Smad1/5, but inhibited that of Smad2/3. Furthermore, SAA attenuated the phosphorylation levels of ERK and Cofilin, which were enhanced by hypoxia. Based on these results, our study indicated that SAA treatment can protect HPAECs from endoMT induced by hypoxia, which may perform via the inhibition on ROS production and further through the downstream effectors of BMPRs or TGF[Formula: see text]R including Smads, ERK and ROCK/cofilin pathways.
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Affiliation(s)
- Tianyi Yuan
- * Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Union Medical College, Beijing 100050, China
| | - Yucai Chen
- * Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Union Medical College, Beijing 100050, China
| | - Huifang Zhang
- * Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Union Medical College, Beijing 100050, China
| | - Lianhua Fang
- * Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Union Medical College, Beijing 100050, China.,† Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Guanhua Du
- * Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Union Medical College, Beijing 100050, China.,† Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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12
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Honoki K. Preventing aging with stem cell rejuvenation: Feasible or infeasible? World J Stem Cells 2017; 9:1-8. [PMID: 28154735 PMCID: PMC5253185 DOI: 10.4252/wjsc.v9.i1.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 08/22/2016] [Accepted: 10/09/2016] [Indexed: 02/06/2023] Open
Abstract
Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging results from the reduced function of effective stem cell populations. Recent advances in aging research have demonstrated that old tissue stem cells can be rejuvenated for the purpose of maintaining the old-organ function by youthful re-calibration of the environment where stem cells reside. Biochemical cues regulating tissue stem cell function include molecular signaling pathways that interact between stem cells themselves and their niches. Historically, plasma fractions have been shown to contain factors capable of controlling age phenotypes; subsequently, signaling pathways involved in the aging process have been identified. Consequently, modulation of signaling pathways such as Notch/Delta, Wnt, transforming growth factor-β, JAK/STAT, mammalian target of rapamycin and p38 mitogen-activated protein kinase has demonstrated potential to rejuvenate stem cell function leading to organismic rejuvenation. Several synthetic agents and natural sources, such as phytochemicals and flavonoids, have been proposed to rejuvenate old stem cells by targeting these pathways. However, several concerns still remain to achieve effective organismic rejuvenation in clinical settings, such as possible carcinogenic actions; thus, further research is still required.
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13
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Zhao Y, Tian B, Sadygov RG, Zhang Y, Brasier AR. Integrative proteomic analysis reveals reprograming tumor necrosis factor signaling in epithelial mesenchymal transition. J Proteomics 2016; 148:126-38. [PMID: 27461979 DOI: 10.1016/j.jprot.2016.07.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 07/07/2016] [Accepted: 07/12/2016] [Indexed: 12/29/2022]
Abstract
UNLABELLED The airway epithelium is a semi-impermeable barrier whose disruption by growth factor reprogramming is associated with chronic airway diseases of humans. Transforming growth factor beta (TGFβ)-induced epithelial mesenchymal transition (EMT) plays important roles in airway remodeling characteristic of idiopathic lung fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Inflammation of the airways leads to airway injury and tumor necrosis factor alpha (TNFα) plays an important pro-inflammatory role. Little systematic information about the effects of EMT on TNFα signaling is available. Using an in vitro model of TGFβ-induced EMT in primary human small airway epithelial cells (hSAECs), we applied quantitative proteomics and phosphoprotein profiling to understand the molecular mechanism of EMT and the impact of EMT on innate inflammatory responses. We quantified 7925 proteins and 1348 phosphorylation sites by stable isotope labeling with iTRAQ technology. We found that cellular response to TNFα is cell state dependent and the relative TNFα response in mesenchymal state is highly compressed. Combined bioinformatics analyses of proteome and phosphoproteome indicate that the EMT state is associated with reprogramming of kinome, signaling cascade of upstream transcription regulators, phosphor-networks, and NF-κB dependent cell signaling. BIOLOGICAL SIGNIFICANCE Epithelial mesenchymal transition and inflammation have important implications for clinical and physiologic manifestations of chronic airway diseases such as severe asthma, COPD, and lung fibrosis. Little systematic information on the interplay between EMT and innate inflammation is available. This study combined quantitative proteomics and phosphorproteomics approach to obtain systems-level insight into the upstream transcription regulators involved in the TGFβ-induced EMT in primary human small airway epithelial cells and to elucidate how EMT impacts on the TNFα signaling pathways. The proteomics and phosphoproteomics analysis indicates that many signaling pathways involved in TGFβ-induced EMT and EMT has profound reprogramming effects on innate inflammation response.
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Affiliation(s)
- Yingxin Zhao
- Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, United States; Institute for Translational Sciences, UTMB, Galveston, TX, United States; Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States.
| | - Bing Tian
- Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, United States; Institute for Translational Sciences, UTMB, Galveston, TX, United States; Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States
| | - Rovshan G Sadygov
- Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States; Department of Biochemistry & Molecular Biology, UTMB, Galveston, TX, United States
| | - Yueqing Zhang
- Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, United States
| | - Allan R Brasier
- Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, United States; Institute for Translational Sciences, UTMB, Galveston, TX, United States; Sealy Center for Molecular Medicine, UTMB, Galveston, TX, United States.
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14
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Abstract
Tgif1 and Tgif2 are transcriptional repressors that inhibit the transcriptional response to transforming growth factor β signaling, and can repress gene expression by direct binding to DNA. Loss of function mutations in TGIF1 are associated with holoprosencephaly (HPE) in humans. In mice, embryos lacking both Tgif1 and Tgif2 fail to complete gastrulation, and conditional double null embryos that survive past gastrulation have HPE and do not survive past mid-gestation. Here we show that in mice of a relatively pure C57BL/6 strain background, loss of Tgif1 alone results in defective axial patterning and altered expression of Hoxc6. The primary defects in Tgif1 null embryos are the presence of extra ribs on the C7 vertebra, consistent with a posterior transformation phenotype. In addition we observed defective cervical vertebrae, primarily C1-C5, in both adult mice and embryos that lacked Tgif1. The combination of Tgif1 and Tgif2 mutations increases the severity and penetrance of the posterior transformation phenotype, without altering the type of defects seen. Similarly, exposure of Tgif1 mutant embryos to retinoic acid at E8.5 increased the severity and penetrance of the Tgif1 phenotype. This suggests that Tgif1 and Tgif2 regulate axial patterning and that reduced TGIF function sensitizes embryos to the effects of retinoic acid.
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15
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Katz LH, Likhter M, Jogunoori W, Belkin M, Ohshiro K, Mishra L. TGF-β signaling in liver and gastrointestinal cancers. Cancer Lett 2016; 379:166-72. [PMID: 27039259 DOI: 10.1016/j.canlet.2016.03.033] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 03/16/2016] [Accepted: 03/18/2016] [Indexed: 02/07/2023]
Abstract
Transforming Growth Factor-β (TGF-β) plays crucial and complex roles in liver and gastrointestinal cancers. These include a multitude of distinct functions, such as maintaining stem cell homeostasis, promoting fibrosis, immune modulating, as a tumor suppressor and paradoxically, as a tumor progressor. However, key mechanisms for the switches responsible for these distinct actions are poorly understood, and remain a challenge. The Cancer Genome Atlas (TCGA) analyses and genetically engineered mouse models now provide an integrated approach to dissect these multifaceted and context-dependent driving roles of the TGF-β pathway. In this review, we will discuss the molecular mechanisms of TGF-β signaling, focusing on colorectal, gastric, pancreatic, and liver cancers. Novel drugs targeting the TGF-β pathway have been developed over the last decade, and some have been proven effective in clinical trials. A better understanding of the TGF-β pathway may improve our ability to target it, thus providing more tools to the armamentarium against these deadly cancers.
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Affiliation(s)
- L H Katz
- Department of Gastroenterology, Sheba Medical Center, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - M Likhter
- Department of Gastroenterology, Sheba Medical Center, Israel
| | - W Jogunoori
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA
| | - M Belkin
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA
| | - K Ohshiro
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA
| | - L Mishra
- Department of Surgery and GWU Cancer Center, George Washington University and DVAMC, Washington, DC, USA.
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16
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Wang J, Shao N, Ding X, Tan B, Song Q, Wang N, Jia Y, Ling H, Cheng Y. Crosstalk between transforming growth factor-β signaling pathway and long non-coding RNAs in cancer. Cancer Lett 2016; 370:296-301. [DOI: 10.1016/j.canlet.2015.11.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 10/11/2015] [Accepted: 11/04/2015] [Indexed: 12/12/2022]
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17
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Ahmed AF, de Bock CE, Lincz LF, Pundavela J, Zouikr I, Sontag E, Hondermarck H, Thorne RF. FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation. Cell Mol Life Sci 2015; 72:4653-69. [PMID: 26104008 PMCID: PMC11113810 DOI: 10.1007/s00018-015-1955-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 12/19/2022]
Abstract
The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are poorly understood. High expression of Fat1 cadherin within the developing neuroepithelium and the manifestation of severe neurological phenotypes in Fat1-knockout mice suggest roles in neurogenesis. Using the SH-SY5Y model of neuronal differentiation and employing gene silencing techniques, we show that FAT1 acts to control neurite outgrowth, also driving cells towards terminal differentiation via inhibitory effects on proliferation. FAT1 actions were shown to be mediated through Hippo signalling where it activated core Hippo kinase components and antagonised functions of the Hippo effector TAZ. Suppression of FAT1 promoted the nucleocytoplasmic shuttling of TAZ leading to enhanced transcription of the Hippo target gene CTGF together with accompanying increases in nuclear levels of Smad3. Silencing of TAZ reversed the effects of FAT1 depletion thus connecting inactivation of TAZ-TGFbeta signalling with Hippo signalling mediated through FAT1. These findings establish FAT1 as a new upstream Hippo element regulating early stages of differentiation in neuronal cells.
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Affiliation(s)
- Abdulrzag F Ahmed
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Charles E de Bock
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
- Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Center for the Biology of Disease, VIB, Leuven, Belgium
| | - Lisa F Lincz
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
- Hunter Haematology Research Group, Calvary Mater Newcastle Hospital, Waratah, NSW, 2298, Australia
| | - Jay Pundavela
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Ihssane Zouikr
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Estelle Sontag
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
- Priority Research Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, NSW, 2308, Australia
| | - Hubert Hondermarck
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, 2308, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Rick F Thorne
- Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia.
- School of Environmental and Life Sciences, University of Newcastle, Ourimbah, NSW, 2258, Australia.
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18
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Cheruku HR, Mohamedali A, Cantor DI, Tan SH, Nice EC, Baker MS. Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer. EUPA OPEN PROTEOMICS 2015. [DOI: 10.1016/j.euprot.2015.06.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Kim D, Lee AS, Jung YJ, Yang KH, Lee S, Park SK, Kim W, Kang KP. Tamoxifen ameliorates renal tubulointerstitial fibrosis by modulation of estrogen receptor α-mediated transforming growth factor-β1/Smad signaling pathway. Nephrol Dial Transplant 2014; 29:2043-53. [PMID: 25031017 DOI: 10.1093/ndt/gfu240] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND After insult to the kidney, a renal fibrotic process is initiated with sustained inflammation, fibroblast activation and accumulation of extracellular matrix (ECM). Tamoxifen has been used as an anti-estrogen for the prevention and treatment of breast cancer. In this study, we investigated the protective effects of tamoxifen on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis and its molecular mechanism. METHODS Renal fibrosis was induced by UUO in 7-week-old C57BL/6 mice. Tamoxifen (50 mg/kg) was given by oral gavage for 5 days before induction of renal fibrosis. Tamoxifen treatment was continued for 14 days after UUO operation. Histologic changes were examined by periodic acid-Schiff stain and Masson's trichrome stain. Expression of α-smooth muscle actin, vimentin, type I collagen, fibronectin and cell adhesion molecules were evaluated by immunohistochemistry and western blot analysis. We also evaluated the effect of tamoxifen on estrogen receptor (ER)-α-mediated transforming growth factor (TGF)-β1/Smad signaling pathway in vitro. RESULTS Renal tubular injury and fibrosis were increased after UUO. Tamoxifen treatment significantly decreased UUO-induced renal tubular injury and fibrosis. Renal fibroblast activation, ECM deposition and inflammation were significantly increased after ureteral ligation. However, tamoxifen treatment significantly decreased UUO-induced renal fibroblast activation, ECM deposition and inflammation by suppression of TGF-β1/Smad signaling pathway in vivo. Tamoxifen decreased TGF-β1-induced fibroblast proliferation and cell migration by modulating ERα-mediated TGF-β1/Smad signaling pathway in vitro. CONCLUSION These findings indicate that tamoxifen has a beneficial effect on UUO-induced tubulointerstitial fibrosis by suppression of renal fibroblast activation via modulation of ERα-mediated renal TGF-β1/Smad signaling pathway.
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Affiliation(s)
- Dal Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Ae Sin Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Yu Jin Jung
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Kyoung Hee Yang
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Sik Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Sung Kwang Park
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Kyung Pyo Kang
- Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea
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20
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Sheen YY, Kim MJ, Park SA, Park SY, Nam JS. Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy. Biomol Ther (Seoul) 2014; 21:323-31. [PMID: 24244818 PMCID: PMC3825194 DOI: 10.4062/biomolther.2013.072] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 09/24/2013] [Indexed: 12/21/2022] Open
Abstract
TGF-β pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-β (TGF-β) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-β related functional contexts. This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression and promotion by TGF-β. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. The TGF-β inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.
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21
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Kremer M, Son G, Zhang K, Moore SM, Norris A, Manzini G, Wheeler MD, Hines IN. Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression. Transpl Int 2014; 27:748-58. [PMID: 24649805 DOI: 10.1111/tri.12322] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 11/24/2013] [Accepted: 03/16/2014] [Indexed: 12/12/2022]
Abstract
Liver regeneration is vital for graft survival and adequate organ function. Smad activation regulates hepatocyte proliferation and macrophage function. The aim of the current study was to evaluate the impact of Smad3 signaling during liver regeneration in the mouse. Male C57Bl/6 wild-type (wt) mice or mice deficient in Smad3 (Smad3(-/-) ) were subjected to a 70% partial hepatectomy (pHx) or sham surgery and sacrificed 24, 42, or 48 h later. Tissue was analyzed for TGF-β signaling, the mitogenic cytokine response [i.e., tumor necrosis factor alpha, TNF-α; interleukin (IL)-6], and liver regeneration. Partial hepatectomy stimulated a strong regenerative response measured by proliferating cell nuclear antigen-positive hepatocytes 42 and 48 h post-pHx in conjunction with an increased expression of IL-6, TNF-α, and Smad2/3 phosphorylation 24 h post-pHx in both hepatocytes and nonparenchymal cells. Surprisingly, Smad3 deficiency led to reduced hepatocyte proliferation 42 h post-pHx which recovered by 48 h, a process that correlated with and was preceded by significant reductions in IL-6 expression and signal transducer and activator of transcription 3 phosphorylation, and cyclin D1 induction 24 h post-pHx. Loss of Smad3 signaling suppresses the expression of key mitogenic cytokines and delays hepatocellular regeneration. Therapies directed at finely regulating Smad3 activation early within the regenerating liver may prove useful in promoting liver cell proliferation and restoration of liver mass.
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Affiliation(s)
- Michael Kremer
- Department of General Surgery, University of Ulm, Ulm, Germany; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA
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22
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Bjerke GA, Pietrzak K, Melhuish TA, Frierson Jr. HF, Paschal BM, Wotton D. Prostate cancer induced by loss of Apc is restrained by TGFβ signaling. PLoS One 2014; 9:e92800. [PMID: 24651496 PMCID: PMC3961420 DOI: 10.1371/journal.pone.0092800] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 02/25/2014] [Indexed: 01/07/2023] Open
Abstract
Recent work with mouse models of prostate cancer (CaP) has shown that inactivation of TGFβ signaling in prostate epithelium can cooperate with deletion of the Pten tumor suppressor to drive locally aggressive cancer and metastatic disease. Here, we show that inactivating the TGFβ pathway by deleting the gene encoding the TGFβ type II receptor (Tgfbr2) in combination with a deletion of the Apc tumor suppressor gene specifically in mouse prostate epithelium, results in the rapid onset of invasive CaP. Micro-metastases were observed in the lymph nodes and lungs of a proportion of the double mutant mice, whereas no metastases were observed in Apc single mutant mice. Prostate-specific Apc;Tgfbr2 mutants had a lower frequency of metastasis and survived significantly longer than Pten;Tgfbr2 double mutants. However, all Apc;Tgfbr2 mutants developed invasive cancer by 30 weeks of age, whereas invasive cancer was rarely observed in Apc single mutant animals, even by one year of age. Further comparison of the Pten and Apc models of CaP revealed additional differences, including adenosquamous carcinoma in the Apc;Tgfbr2 mutants that was not seen in the Pten model, and a lack of robust induction of the TGFβ pathway in Apc null prostate. In addition to causing high-grade prostate intra-epithelial neoplasia (HGPIN), deletion of either Pten or Apc induced senescence in affected prostate ducts, and this restraint was overcome by loss of Tgfbr2. In summary, this work demonstrates that TGFβ signaling restrains the progression of CaP induced by different tumor suppressor mutations, suggesting that TGFβ signaling exerts a general tumor suppressive effect in prostate.
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Affiliation(s)
- Glen A. Bjerke
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America
| | - Karolina Pietrzak
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Cytobiochemistry, University of Lodz, Lodz, Poland
| | - Tiffany A. Melhuish
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America
| | - Henry F. Frierson Jr.
- Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America
| | - Bryce M. Paschal
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America
| | - David Wotton
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail:
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23
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TGF-β signaling in stem cells and tumorigenesis. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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24
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Bjerke GA, Yang CS, Frierson HF, Paschal BM, Wotton D. Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. Oncogene 2013; 33:3660-7. [PMID: 23995785 PMCID: PMC3939071 DOI: 10.1038/onc.2013.342] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 06/28/2013] [Accepted: 07/05/2013] [Indexed: 12/16/2022]
Abstract
Mutations in the PTEN tumor suppressor gene are found in a high proportion of human prostate cancers, and in mice, Pten deletion induces high-grade prostate intra-epithelial neoplasia (HGPIN). However, progression from HGPIN to invasive cancer occurs slowly, suggesting that tumorigenesis is subject to restraint. We show that Pten deletion, or constitutive activation of the downstream kinase AKT, activates the transforming growth factor (TGF) β pathway in prostate epithelial cells. TGFβ signaling is known to play a tumor suppressive role in many cancer types, and reduced expression of TGFβ receptors correlates with advanced human prostate cancer. We demonstrate that in combination either with loss of Pten, or expression of constitutively active AKT1, inactivation of TGFβ signaling by deletion of the TGFβ type II receptor gene relieves a restraint on tumorigenesis. This results in rapid progession to lethal prostate cancer, including metastasis to lymph node and lung. In prostate epithelium, inactivation of TGFβ signaling alone is insufficient to initiate tumorigenesis, but greatly accelerates cancer progression. The activation of TGFβ signaling by Pten loss or AKT activation suggests that the same signaling events that play key roles in tumor initiation also induce the activity of a pathway that restrains disease progression.
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Affiliation(s)
- G A Bjerke
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA
| | - C-S Yang
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA
| | - H F Frierson
- Department of Pathology, University of Virginia, Charlottesville, VA USA
| | - B M Paschal
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA
| | - D Wotton
- Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA
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Pawlus MR, Hu CJ. Enhanceosomes as integrators of hypoxia inducible factor (HIF) and other transcription factors in the hypoxic transcriptional response. Cell Signal 2013; 25:1895-903. [PMID: 23707522 PMCID: PMC3700616 DOI: 10.1016/j.cellsig.2013.05.018] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 05/07/2013] [Indexed: 12/27/2022]
Abstract
Hypoxia is a prevalent attribute of the solid tumor microenvironment that promotes the expression of genes through posttranslational modifications and stabilization of alpha subunits (HIF1α and HIF2α) of hypoxia-inducible factors (HIFs). Despite significant similarities, HIF1 (HIF1α/ARNT) and HIF2 (HIF2α/ARNT) activate common as well as unique target genes and exhibit different functions in cancer biology. More surprisingly, accumulating data indicates that the HIF1- and/or HIF2-mediated hypoxia responses can be oncogenic as well as tumor suppressive. While the role of HIF in the hypoxia response is well established, recent data support the concept that HIF is necessary, but not sufficient for the hypoxic response. Other transcription factors that are activated by hypoxia are also required for the HIF-mediated hypoxia response. HIFs, other transcription factors, co-factors and RNA poll II recruited by HIF and other transcription factors form multifactorial enhanceosome complexes on the promoters of HIF target genes to activate hypoxia inducible genes. Importantly, HIF1 or HIF2 requires distinct partners in activating HIF1 or HIF2 target genes. Because HIF enhanceosome formation is required for the gene activation and distinct functions of HIF1 and HIF2 in tumor biology, disruption of the HIF1 or HIF2 specific enhanceosome complex may prove to be a beneficial strategy in tumor treatment in which tumor growth is specifically dependent upon HIF1 or HIF2 activity.
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Affiliation(s)
- Matthew R. Pawlus
- Molecular Biology Graduate Program University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Cheng-Jun Hu
- Molecular Biology Graduate Program University of Colorado Anschutz Medical Campus, Aurora, CO 80045
- Department of Craniofacial Biology University of Colorado Anschutz Medical Campus, Aurora, CO 80045
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Abstract
INTRODUCTION The transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β pathway are crucial in developing TGF-β-based therapeutics for cancer. AREAS COVERED This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given. EXPERT OPINION Targeting the TGF-β pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-β and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-β in each specific tumor. Future studies are needed in order to find safer and more effective TGF-β-based drugs.
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Affiliation(s)
- Lior H Katz
- Visiting Scientist, The University of Texas, M.D. Anderson Cancer Center, Department of Gastroenterology, Hepatology, & Nutrition, Houston, TX, USA
| | - Ying Li
- Assistant Professor (Research), The University of Texas, M. D. Anderson Cancer Center, Department of Gastroenterology, Hepatology, & Nutrition, Dr. Lopa Mishra’s Lab, Houston, TX, USA
| | - Jiun-Sheng Chen
- Research Assistant II, The University of Texas, M.D. Anderson Cancer Center, Department of Gastroenterology, Hepatology, & Nutrition, Dr. Lopa Mishra’s Lab, Houston, TX, USA
| | - Nina M Muñoz
- Research Scientist, The University of Texas, M.D. Anderson Cancer Center, Department of Gastroenterology, Hepatology, & Nutrition, Dr. Lopa Mishra’s Lab, Houston, TX, USA
| | - Avijit Majumdar
- Postdoctoral Fellow, The University of Texas, M.D. Anderson Cancer Center, Department of Gastroenterology, Hepatology, & Nutrition, Dr.Lopa Mishra’s Lab, Houston, TX, USA
| | - Jian Chen
- Instructor, The University of Texas, M.D. Anderson Cancer Center, Department of Gastroenterology, Hepatology, & Nutrition, Houston, TX, USA
| | - Lopa Mishra
- Del and Dennis McCarthy Distinguished Professor and Chair, The University of Texas, M.D. Anderson Cancer Center, Department of Gastroenterology, Hepatology, & Nutrition, Houston, TX, USA, Tel: +1 713 794 3221; Fax: +1 713 745 1886
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Cao Y, Zhang W, Gao X, Zhang G, Falzon M, Townsend CM, Hellmich MR, Ko TC. PTHrP is a novel mediator for TGF-β-induced apoptosis. ACTA ACUST UNITED AC 2013; 184:40-6. [PMID: 23499802 DOI: 10.1016/j.regpep.2013.03.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 10/23/2012] [Accepted: 03/03/2013] [Indexed: 02/04/2023]
Abstract
Parathyroid hormone-related protein (PTHrP) is a polyhormone secretory protein that plays fundamental roles in the development and function of various tissues. Transforming growth factor (TGF)-β is an important tumor suppressor that induces cell cycle arrest and apoptosis. Increased PTHrP expression has been implicated in TGF-β-induced growth inhibition in human hepatocellular carcinoma cells. However, whether PTHrP is involved in TGF-β-induced apoptosis remains unknown. Using Hep3B and HuH-7, two human hepatocellular carcinoma cell lines, the current study examined the hypothesis that TGF-β-induced apoptosis is mediated by the induction of PTHrP expression. We found that (1) TGF-β induces PTHrP mRNA expression, protein expression and secretion in a time-dependent fashion; (2) knockdown of PTHrP gene expression or neutralization of secreted PTHrP isoforms blocks TGF-β-induced apoptosis; and (3) TGF-β-induced PTHrP expression is Smad3-dependent. Thus, we have identified PTHrP as a novel mediator for TGF-β-induced apoptosis in Hep3B cells. Our findings provide further insights into the mechanisms through which TGF-β conveys tumor suppression activity.
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Affiliation(s)
- Yanna Cao
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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Kamato D, Burch ML, Osman N, Zheng W, Little PJ. Therapeutic implications of endothelin and thrombin G-protein-coupled receptor transactivation of tyrosine and serine/threonine kinase cell surface receptors. J Pharm Pharmacol 2012; 65:465-73. [DOI: 10.1111/j.2042-7158.2012.01577.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Abstract
Objectives
This review discusses the latest developments in G protein coupled receptor (GPCR) signalling related to the transactivation of cell surface protein kinase receptors and the therapeutic implications.
Key findings
Multiple GPCRs have been known to transactivate protein tyrosine kinase receptors for almost two decades. More recently it has been discovered that GPCRs can also transactivate protein serine/threonine kinase receptors such as that for transforming growth factor (TGF)-β. Using the model of proteoglycan synthesis and glycosaminoglycan elongation in human vascular smooth muscle cells which is a component of an in vitro model of atherosclerosis, the dual tyrosine and serine/threonine kinase receptor transactivation pathways appear to account for all of the response to the agonists, endothelin and thrombin.
Summary
The broadening of the paradigm of GPCR receptor transactivation explains the broad range of activities of these receptors and also the efficacy of GPCR antagonists in cardiovascular therapeutics. Deciphering the mechanisms of transactivation with the aim of identifying a common therapeutic target remains the next challenge.
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Affiliation(s)
- Danielle Kamato
- Discipline of Pharmacy, School of Medical Sciences, Australia
- Diabetes Complications Group, Metabolism, Exercise and Disease Program, Health Innovations Research Institute, RMIT University, Melbourne, Australia
| | - Micah L Burch
- Diabetes Complications Group, Metabolism, Exercise and Disease Program, Health Innovations Research Institute, RMIT University, Melbourne, Australia
- Department of Medicine, Monash University School of Medicine (Central and Eastern Clinical School, Alfred Health), Prahran VIC, Australia
| | - Narin Osman
- Discipline of Pharmacy, School of Medical Sciences, Australia
- Diabetes Complications Group, Metabolism, Exercise and Disease Program, Health Innovations Research Institute, RMIT University, Melbourne, Australia
| | - Wenhua Zheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Peter J Little
- Discipline of Pharmacy, School of Medical Sciences, Australia
- Diabetes Complications Group, Metabolism, Exercise and Disease Program, Health Innovations Research Institute, RMIT University, Melbourne, Australia
- Department of Medicine, Monash University School of Medicine (Central and Eastern Clinical School, Alfred Health), Prahran VIC, Australia
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c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression. Nat Cell Biol 2012; 14:727-37. [PMID: 22729085 DOI: 10.1038/ncb2528] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Accepted: 05/22/2012] [Indexed: 11/08/2022]
Abstract
Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1-Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16(INK4a). c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16(INK4a) upregulation and osteoblast senescence. Mouse genetic studies revealed that p16(INK4a) controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16(INK4a) expression and osteoprogenitor expansion.
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Cieslik KA, Trial J, Entman ML. Defective myofibroblast formation from mesenchymal stem cells in the aging murine heart rescue by activation of the AMPK pathway. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:1792-806. [PMID: 21819956 DOI: 10.1016/j.ajpath.2011.06.022] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 06/16/2011] [Accepted: 06/21/2011] [Indexed: 11/18/2022]
Abstract
Aged mice in a murine model of myocardial infarction exhibit less effective myocardial repair. We hypothesized that the deficiency arises from altered lineage choice of endogenous mesenchymal stem cells (MSCs) and faulty maturation of myofibroblasts. Examination of cardiac MSCs revealed a substantial reduction in the pluripotency marker Nanog in cells from aged mice. In addition, the aged MSCs demonstrated a redirected lineage choice that favored adipocytic commitment over fibroblast or myofibroblast differentiation. Fibroblasts derived from aged MSCs demonstrated reduced expression of transforming growth factor-β (TGF-β) receptors I and II and diminished SMAD3 phosphorylation, associated with attenuated contractility and migration. Overexpression of constitutively active TGF-β receptor I in aged cardiac fibroblasts ameliorated their defective motility but did not improve their contractility. Culturing of MSCs and fibroblasts with AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside) to activate adenosine monophosphate-activated kinase resulted in TGF-β-dependent development of myofibroblasts with markedly enhanced contractility despite no reduction in adipocytic commitment or increased expression of TGF-β receptors and SMAD3 phosphorylation. The data suggest an adenosine monophosphate-activated kinase-dependent gain of function as mediated by phosphorylation of TGF-β-activated kinase 1 and p38 mitogen-activated protein kinase, which amplifies the response to TGF-β1 via a non-canonical pathway, thus compensating for the reduced expression of TGF-β receptors.
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Affiliation(s)
- Katarzyna A Cieslik
- Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine and the Methodist Hospital, Houston, TX 77030, USA
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Cao Y, Gao X, Zhang W, Zhang G, Nguyen AK, Liu X, Jimenez F, Cox CS, Townsend CM, Ko TC. Dietary fiber enhances TGF-β signaling and growth inhibition in the gut. Am J Physiol Gastrointest Liver Physiol 2011; 301:G156-64. [PMID: 21454444 PMCID: PMC3129933 DOI: 10.1152/ajpgi.00362.2010] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dietary fiber intake links to decreased risk of colorectal cancers. The underlying mechanisms remain unclear. Recently, we found that butyrate, a short-chain fatty acid produced in gut by bacterial fermentation of dietary fiber, enhances TGF-β signaling in rat intestinal epithelial cells (RIE-1). Furthermore, TGF-β represses inhibitors of differentiation (Ids), leading to apoptosis. We hypothesized that dietary fiber enhances TGF-β's growth inhibitory effects on gut epithelium via inhibition of Id2. In this study, Balb/c and DBA/2N mice were fed with a regular rodent chow or supplemented with a dietary fiber (20% pectin) and Smad3 level in gut epithelium was measured. In vitro, RIE-1 cells were treated with butyrate and TGF-β(1), and cell functions were evaluated. Furthermore, the role of Ids in butyrate- and TGF-β-induced growth inhibition was investigated. We found that pectin feeding increased Smad3 protein levels in the jejunum (1.47 ± 0.26-fold, P = 0.045, in Balb/c mice; 1.49 ± 0.19-fold, P = 0.016, in DBA/2N mice), and phospho-Smad3 levels (1.92 ± 0.27-fold, P = 0.009, in Balb/c mice; 1.83 ± 0.28-fold, P = 0.022, in DBA/2N mice). Butyrate or TGF-β alone inhibited cell growth and induced cell cycle arrest. The combined treatment of butyrate and TGF-β synergistically induced cell cycle arrest and apoptosis in RIE-1 cells and repressed Id2 and Id3 levels. Furthermore, knockdown of Id2 gene expression by use of small interfering RNA caused cell cycle arrest and apoptosis. We conclude that dietary fiber pectin enhanced Smad3 expression and activation in the gut. Butyrate and TGF-β induced cell cycle arrest and apoptosis, which may be mediated by repression of Id2. Our results implicate a novel mechanism of dietary fiber in reducing the risk of colorectal cancer development.
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Affiliation(s)
| | | | | | | | | | | | - Fernando Jimenez
- 2Pediatric Surgery, University of Texas Health Science Center at Houston, Houston; and
| | - Charles S. Cox
- 2Pediatric Surgery, University of Texas Health Science Center at Houston, Houston; and
| | | | - Tien C. Ko
- Departments of 1Surgery and ,3Department of Surgery, University of Texas Medical Branch, Galveston, Texas
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Li L, Orner BP, Huang T, Hinck AP, Kiessling LL. Peptide ligands that use a novel binding site to target both TGF-β receptors. MOLECULAR BIOSYSTEMS 2010; 6:2392-402. [PMID: 20890540 PMCID: PMC3064480 DOI: 10.1039/c0mb00115e] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The transforming growth factor beta (TGF-β) signaling pathway plays myriad roles in development and disease. TGF-β isoforms initiate signaling by organizing their cell surface receptors TβRI and TβRII. Exploration and exploitation of the versatility of TGF-β signaling requires an enhanced understanding of structure-function relationships in this pathway. To this end, small molecule, peptide, and antibody effectors that bind key signaling components would serve as valuable probes. We focused on the extracellular domain of TβR1 (TβRI-ED) as a target for effector screening. The observation that TβRI-ED can bind to a TGF-β coreceptor (endoglin) suggests that the TβRI-ED may have multiple interaction sites. Using phage display, we identified two peptides LTGKNFPMFHRN (Pep1) and MHRMPSFLPTTL (Pep2) that bind the TβRI-ED (K(d)≈ 10(-5) M). Although our screen focused on TβRI-ED, the hit peptides interact with the TβRII-ED with similar affinities. The peptide ligands occupy the same binding sites on TβRI and TβRII, as demonstrated by their ability to compete with each other for receptor binding. Moreover, neither interferes with TGF-β binding. These results indicate that both TβRI and TβRII possess hot spots for protein-protein interactions that are distinct from those used by their known ligand TGF-β. To convert these compounds into high affinity probes, we exploited the observation that TβRI and TβRII exist as dimers on the cell surface; therefore, we assembled a multivalent ligand. Specifically, we displayed one of our receptor-binding peptides on a dendrimer scaffold. We anticipate that the potent multivalent ligand that resulted can be used to probe the role of receptor assembly in TGF-β function.
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Affiliation(s)
- Lingyin Li
- Department of Chemistry and Biochemistry, University of Wisconsin, Madison, WI 53706, USA
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Gil PR, Japtok L, Kleuser B. Sphingosine 1-phosphate mediates chemotaxis of human primary fibroblasts via the S1P-receptor subtypes S1P1 and S1P3 and Smad-signalling. Cytoskeleton (Hoboken) 2010; 67:773-83. [DOI: 10.1002/cm.20486] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Revised: 08/26/2010] [Accepted: 09/09/2010] [Indexed: 11/09/2022]
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Analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas. J Neurooncol 2010; 103:277-85. [DOI: 10.1007/s11060-010-0399-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Accepted: 08/31/2010] [Indexed: 12/14/2022]
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Targeting Smad4 links microRNA-146a to the TGF-beta pathway during retinoid acid induction in acute promyelocytic leukemia cell line. Int J Hematol 2010; 92:129-35. [PMID: 20577838 DOI: 10.1007/s12185-010-0626-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2010] [Revised: 05/13/2010] [Accepted: 06/01/2010] [Indexed: 02/05/2023]
Abstract
The expression pattern of microRNAs (miRNAs) and their potential target genes were investigated in acute promyelocytic leukemia (APL) cell line NB4 cells during all-trans-retinoid acid (ATRA) treatment by using a miRNA microarrays platform and real-time quantitative PCR (RTQ-PCR). MiR-146a as one of the miRNAs down-regulated by ATRA during APL differentiation was identified. Direct interaction between miR146a and its predictive target gene Smad4 were confirmed by Luciferase assay. Down-regulation of miR-146a and upregulation of Smad4 at protein levels were demonstrated. These data suggested that miR-146a might influence proliferation of APL cells through TGF-beta1/Smad signal transduction pathway during ATRA induction.
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Kurpinski K, Lam H, Chu J, Wang A, Kim A, Tsay E, Agrawal S, Schaffer DV, Li S. Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells. Stem Cells 2010; 28:734-42. [PMID: 20146266 DOI: 10.1002/stem.319] [Citation(s) in RCA: 197] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The differentiation of stem cells into smooth muscle cells (SMCs) plays an important role in vascular development and remodeling. In addition, stem cells represent a potential source of SMCs for regenerative medicine applications such as constructing vascular grafts. Previous studies have suggested that various biochemical factors, including transforming growth factor-beta (TGF-beta) and the Notch pathway, may play important roles in vascular differentiation. However, the interactions of these two signaling pathways in the differentiation of bone marrow mesenchymal stem cells (MSCs) have not been clearly defined. In this study, we profiled the gene expression in MSCs in response to TGF-beta, and showed that TGF-beta induced Notch ligand Jagged 1 (JAG1) and SMC markers, including smooth muscle alpha-actin (ACTA2), calponin 1 (CNN1), and myocardin (MYOCD), which were dependent on the activation of SMAD3 and Rho kinase. In addition, knocking down JAG1 expression partially blocked ACTA2 and CNN1 expression and completely blocked MYOCD expression, suggesting that JAG1 plays an important role in TGF-beta-induced expression of SMC markers. On the other hand, the activation of Notch signaling induced the expression of SMC markers in MSCs and human embryonic stem cells (hESCs). Notch activation in hESCs also resulted in an increase of neural markers and a decrease of endothelial markers. These results suggest that Notch signaling mediates TGF-beta regulation of MSC differentiation and that Notch signaling induces the differentiation of MSCs and hESCs into SMCs, which represents a novel mechanism involved in stem cell differentiation.
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Affiliation(s)
- Kyle Kurpinski
- Joint Graduate Program in Bioengineering, University of California Berkeley, Berkeley, California, USA
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Albrecht ED, Pepe GJ. Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy. THE INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY 2010; 54:397-408. [PMID: 19876841 DOI: 10.1387/ijdb.082758ea] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
During human and nonhuman primate pregnancy, an extensive blood vessel network is established within the villous placenta to support fetal growth and follicles develop within the fetal ovary to provide a pool of oocytes for reproductive function in adulthood. These two important developmental events occur in association with a progressive increase in placental estrogen production and levels. This review will describe the developmental processes required for placental vascularization and fetal follicular maturation and recent studies which show that estrogen has an important role in regulating these events.
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Affiliation(s)
- Eugene D Albrecht
- Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Studies in Reproduction, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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Correlations between gene expression and mercury levels in blood of boys with and without autism. Neurotox Res 2009; 19:31-48. [PMID: 19937285 PMCID: PMC3006666 DOI: 10.1007/s12640-009-9137-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Revised: 10/15/2009] [Accepted: 11/10/2009] [Indexed: 01/23/2023]
Abstract
Gene expression in blood was correlated with mercury levels in blood of 2- to 5-year-old boys with autism (AU) compared to age-matched typically developing (TD) control boys. This was done to address the possibility that the two groups might metabolize toxicants, such as mercury, differently. RNA was isolated from blood and gene expression assessed on whole genome Affymetrix Human U133 expression microarrays. Mercury levels were measured using an inductively coupled plasma mass spectrometer. Analysis of covariance (ANCOVA) was performed and partial correlations between gene expression and mercury levels were calculated, after correcting for age and batch effects. To reduce false positives, only genes shared by the ANCOVA models were analyzed. Of the 26 genes that correlated with mercury levels in both AU and TD boys, 11 were significantly different between the groups (P(Diagnosis*Mercury) ≤ 0.05). The expression of a large number of genes (n = 316) correlated with mercury levels in TD but not in AU boys (P ≤ 0.05), the most represented biological functions being cell death and cell morphology. Expression of 189 genes correlated with mercury levels in AU but not in TD boys (P ≤ 0.05), the most represented biological functions being cell morphology, amino acid metabolism, and antigen presentation. These data and those in our companion study on correlation of gene expression and lead levels show that AU and TD children display different correlations between transcript levels and low levels of mercury and lead. These findings might suggest different genetic transcriptional programs associated with mercury in AU compared to TD children.
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Jin Q, Gao G, Mulder KM. Requirement of a dynein light chain in TGFbeta/Smad3 signaling. J Cell Physiol 2009; 221:707-15. [PMID: 19711352 DOI: 10.1002/jcp.21910] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We have previously reported that the dynein light chain (DLC) km23-1 is required for Smad2-dependent TGFbeta signaling. Here we describe another member of the km23/DYNLRB/LC7/robl family of DLCs, termed km23-2, which is also involved in TGFbeta signaling. We show not only that TGFbeta stimulates the interaction of km23-2 (DYNLRB2) with TGFbeta receptor II (TbetaRII) but also that TGFbeta regulates the interaction between km23-2 and endogenous TbetaRII in vivo. In addition, TGFbeta treatment causes km23-2 phosphorylation, whereas a kinase-deficient form of TbetaRII prevents km23-2 phosphorylation. In contrast to the km23-1 isoform, blockade of km23-2 expression using small interfering RNAs (siRNAs) decreased key TGFbeta/Smad3-specific responses, including the induction of both plasminogen activator inhibitor-1 (PAI-1) gene expression and p21 protein expression. Blockade of km23-1 expression had no effect on these two major TGFbeta/Smad3 responses under similar conditions. Further, km23-2 was required for TGFbeta stimulation of Smad3-dependent Smad-binding element (SBE)2-Luc transcriptional activity, but not for TGFbeta stimulation of Smad2-dependent activin responsive element (ARE)-Lux transcriptional activity. In order to assess the mechanisms underlying the preferential stimulation of Smad3- versus Smad2-specific TGFbeta responses, immunoprecipitation (IP)/blot analyses were performed, which demonstrate that TGFbeta stimulated preferential complex formation of km23-2 with Smad3, relative to Smad2. Collectively, our findings indicate that km23-2 is required for Smad3-dependent TGFbeta signaling. More importantly, we demonstrate that km23-2 has functions in TGFbeta signaling that are distinct from those for km23-1. This is the first report to describe a differential requirement for unique isoforms of a specific DLC family in Smad-specific TGFbeta signaling.
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Affiliation(s)
- Qunyan Jin
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
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Shih WL, Liao MH, Lin PY, Chang CI, Cheng HL, Yu FL, Lee JW. PI 3-kinase/Akt and STAT3 are required for the prevention of TGF-beta-induced Hep3B cell apoptosis by autocrine motility factor/phosphoglucose isomerase. Cancer Lett 2009; 290:223-37. [PMID: 19819066 DOI: 10.1016/j.canlet.2009.09.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2009] [Revised: 09/16/2009] [Accepted: 09/17/2009] [Indexed: 11/17/2022]
Abstract
We established Hep3B cells stably-expressing wild-type and mutated AMF/PGI with differing enzymatic activities in order to investigate how AMF/PGI affects TGF-beta-induced apoptosis, and demonstrated that AMF/PGI against TGF-beta-induced apoptosis was correlated with its enzymatic activity. AMF/PGI did not alter TGF-beta-receptor expression nor affect TGF-beta-induced PAI-1 gene promoter or Smad3/4 activity. AMF/PGI induced PI 3-kinase activity, IRS and Akt phosphorylation, which can further regulate BAD phosphorylation. Constitutively-active p110 enhanced AMF/PGI-mediated anti-apoptosis activity, and dominant negative Akt alleviated anti-TGF-beta-induced apoptosis. We also demonstrated that STAT3 is a weak anti-apoptotic agent but has an increased anti-apoptotic effect in cooperation with PI 3-kinase/Akt.
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Affiliation(s)
- Wen-Ling Shih
- National Pingtung University of Science and Technology, Taiwan.
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A continuous observation of the degenerative process in the intervertebral disc of Smad3 gene knock-out mice. Spine (Phila Pa 1976) 2009; 34:1363-9. [PMID: 19478656 DOI: 10.1097/brs.0b013e3181a3c7c7] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Pathologic changes were observed in the spine of small mother against decapentaplegic (Smad) 3 mice at different time points. OBJECTIVE To observe the degeneration of the intervertebral disc (IVD) in Smad3 gene knock-out mice with growth. SUMMARY OF BACKGROUND DATA Smad3 gene knock-out (Smad3) mice displays phenotypes similar to human osteoarthritis. Despite the similarities between IVD cartilage endplate and the articular cartilage, there has been relatively little interest in exploring the possibility that IVD degeneration might be driven by the deficiency of Smad3. METHODS The Smad3 mice were killed at the 10th, 30th, and 60th day after their birth and the IVD samples of spine were harvested for histologic and immunohistochemical studies. Total RNA isolated from these samples were used for real-time PCR analysis of type II collagen (Col2alpha1), type X collagen (Col10alpha1), aggrecan, and transforming growth factor-beta1 (TGF-beta1). RESULTS Compared with the wild-type mice, Smad3 mice appeared significantly smaller in size. Radiograph showed that the spine of Smad3 mice is malformation and kyphosis. Histologic analysis revealed the declined height of cartilage endplate, decreased proteoglycan and collagen content in disc of Smad3 mice. With growth, especially of the 30- and 60-day old Smad3 mice, the protein positive staining of type II collagen, aggrecan, and TGF-beta1 in the disc decreased, while that of type X collagen increased. And the analysis of real-time PCR showed that the mRNA expression of Col2alpha1, aggrecan, and TGF-beta1 decreased, while that of Col10alpha1 increased. CONCLUSION Smad3 gene knock-out mice develop IVD degeneration with growth.
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Fleming JAGW, Song G, Choi Y, Spencer TE, Bazer FW. Interferon regulatory factor 6 (IRF6) is expressed in the ovine uterus and functions as a transcriptional activator. Mol Cell Endocrinol 2009; 299:252-60. [PMID: 19022341 PMCID: PMC2655364 DOI: 10.1016/j.mce.2008.10.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Revised: 10/17/2008] [Accepted: 10/21/2008] [Indexed: 11/30/2022]
Abstract
Interferon tau (IFNT), the maternal recognition of pregnancy signal in sheep and other ruminants, is secreted by the conceptus and regulates the expression of a number of genes in a cell-specific manner within the uterus. The response of different endometrial cell types to IFNT appears to be specified by IFN regulatory factors (IRFs). IRF2, a potent repressor of gene transcription, is expressed only by luminal (LE) and superficial glandular epithelia (sGE), whereas IRF1 and IRF9, activators of gene transcription, are expressed only in GE and stromal cells of the uterus during early pregnancy. In the present study, IRF6 was found to be expressed in LE/sGE and middle GE of the ovine uterine endometrium as well as conceptus trophectoderm. IRF family members can regulate transcription via IFN-stimulated response elements (ISREs). Transient transfection analyses found that IRF6 enhanced basal activity of ISRE-containing promoters, but did not enhance IFNT stimulation of ISRE-containing promoters in variety of different cell types. Further, IRF6 did not cooperate with IRF1 or reduce IRF2 repression of ISRE-containing promoter activity. These results establish that IRF6 is a transcriptional activator that is preferentially expressed in the endometrial epithelia and conceptus trophectoderm. IRF6 is hypothesized to play critical roles in endometrial gene expression as well as in conceptus trophectoderm growth and differentiation.
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Affiliation(s)
- Jo-Ann G W Fleming
- Center for Animal Biotechnology and Genomics and Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
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Carlson ME, Silva HS, Conboy IM. Aging of signal transduction pathways, and pathology. Exp Cell Res 2008; 314:1951-61. [PMID: 18474281 DOI: 10.1016/j.yexcr.2008.03.017] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Revised: 03/26/2008] [Accepted: 03/29/2008] [Indexed: 12/15/2022]
Abstract
The major cell signaling pathways, and their specific mechanisms of transduction, have been a subject of investigation for many years. As our understanding of these pathways advances, we find that they are evolutionarily well-conserved not only individually, but also at the level of their crosstalk and signal integration. Productive interactions within the key signal transduction networks determine success in embryonic organogenesis, and postnatal tissue repair throughout adulthood. However, aside from clues revealed through examining age-related degenerative diseases, much remains uncertain about imbalances within these pathways during normal aging. Further, little is known about the molecular mechanisms by which alterations in the major cell signal transduction networks cause age-related pathologies. The aim of this review is to describe the complex interplay between the Notch, TGFbeta, WNT, RTK-Ras and Hh signaling pathways, with a specific focus on the changes introduced within these networks by the aging process, and those typical of age-associated human pathologies.
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Affiliation(s)
- Morgan E Carlson
- Department of Bioengineering, University of California, Berkeley, Berkeley, California 94720-1762, USA.
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Kojima T, Takano KI, Yamamoto T, Murata M, Son S, Imamura M, Yamaguchi H, Osanai M, Chiba H, Himi T, Sawada N. Transforming growth factor-beta induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes. Liver Int 2008; 28:534-45. [PMID: 18031476 DOI: 10.1111/j.1478-3231.2007.01631.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Transforming growth factor-beta (TGF-beta) initiates and maintains epithelial-mesenchymal transition (EMT), which causes disassembly of tight junctions and loss of epithelial cell polarity. In mature hepatocytes during EMT induced by TGF-beta, changes in the expression of tight junction proteins and the fence function indicated that epithelial cell polarity remains unclear. METHODS In the present study, using primary cultures of adult rat hepatocytes at day 10 after plating, in which epithelial cell polarity is well maintained by tight junctions, we examined the effects of 0.01-20 ng/ml TGF-beta on the expression of the integral tight junction proteins, claudin-1, -2 and occludin, as well as the fence function. RESULTS In adult rat hepatocytes, TGF-beta induced EMT, which was indicated as upregulation of Smad-interacting protein-1 (SIP1) and Snail and down-regulation of E-cadherin. Down-regulation of claudin-1 and upregulation of occludin were observed beginning from a low dose of TGF-beta, whereas upregulation of claudin-2 was observed at a high dose of TGF-beta. Furthermore, treatment with TGF-beta caused disruption of the fence function, which was closely associated with the expression of claudin-1 via p38 mitogen-activated protein kinase (MAPK), phosphoinositide-3 kinase and protein kinase C but not MAPK signalling pathways. CONCLUSION These results suggest that in mature hepatocytes in vitro, TGF-beta induces EMT by down-regulation of claudin-1 and the fence function via distinct signalling pathways.
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Affiliation(s)
- Takashi Kojima
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
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Yu J, Zhang L, Chen A, Xiang G, Wang Y, Wu J, Mitchelson K, Cheng J, Zhou Y. Identification of the gene transcription and apoptosis mediated by TGF-beta-Smad2/3-Smad4 signaling. J Cell Physiol 2008; 215:422-33. [PMID: 17960585 DOI: 10.1002/jcp.21325] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. However, the signaling functions of Smad2/3-Smad4 during TGF-beta-induced responses are obscure as TGF-beta also initiates a number of other signaling pathways. In this study, we systematically assessed the contribution of TGF-beta-Smad2/3-Smad4 signaling to both target gene transcription and apoptosis. Individual Smads were selectively knocked down in Hep3B cells by stable RNA interference (RNAi). We identified TGF-beta-responsive genes using genome-wide oligonucleotide microarrays and confirmed their dependency on Smad2, Smad3, or Smad4 by the combination of RNAi and microarray assay. The major finding from our microarray analysis was that of the 2,039 target genes seen to be regulated via TGF-beta induction, 190 were differentially transcriptionally controlled by Smad2-Smad4 and Smad3-Smad4 signaling and the latter control mechanism appeared to be functionally more important. We also found indirect evidence of competition between Smad2 and Smad3 for their activation when controlling the transcription of target genes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells.
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Affiliation(s)
- Jian Yu
- Medical Systems Biology Research Center, Tsinghua University, Beijing, China
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Chang R, Brauer W, Stetter M. Modeling semantics of inconsistent qualitative knowledge for quantitative Bayesian network inference. Neural Netw 2007; 21:182-92. [PMID: 18272332 DOI: 10.1016/j.neunet.2007.12.042] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Revised: 11/27/2007] [Accepted: 12/11/2007] [Indexed: 12/01/2022]
Abstract
We propose a novel framework for performing quantitative Bayesian inference based on qualitative knowledge. Here, we focus on the treatment in the case of inconsistent qualitative knowledge. A hierarchical Bayesian model is proposed for integrating inconsistent qualitative knowledge by calculating a prior belief distribution based on a vector of knowledge features. Each inconsistent knowledge component uniquely defines a model class in the hyperspace. A set of constraints within each class is generated to describe the uncertainty in ground Bayesian model space. Quantitative Bayesian inference is approximated by model averaging with Monte Carlo methods. Our method is firstly benchmarked on ASIA network and is applied to a realistic biomolecular interaction modeling problem for breast cancer bone metastasis. Results suggest that our method enables consistently modeling and quantitative Bayesian inference by reconciling a set of inconsistent qualitative knowledge.
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Affiliation(s)
- Rui Chang
- Department of Computer Science, Technical University of Munich, Germany.
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Morris SA, Almeida AD, Tanaka H, Ohta K, Ohnuma SI. Tsukushi modulates Xnr2, FGF and BMP signaling: regulation of Xenopus germ layer formation. PLoS One 2007; 2:e1004. [PMID: 17925852 PMCID: PMC1994590 DOI: 10.1371/journal.pone.0001004] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Accepted: 09/11/2007] [Indexed: 11/28/2022] Open
Abstract
Background Cell-cell communication is essential in tissue patterning. In early amphibian development, mesoderm is formed in the blastula-stage embryo through inductive interactions in which vegetal cells act on overlying equatorial cells. Members of the TGF-β family such as activin B, Vg1, derrière and Xenopus nodal-related proteins (Xnrs) are candidate mesoderm inducing factors, with further activity to induce endoderm of the vegetal region. TGF-β-like ligands, including BMP, are also responsible for patterning of germ layers. In addition, FGF signaling is essential for mesoderm formation whereas FGF signal inhibition has been implicated in endoderm induction. Clearly, several signaling pathways are coordinated to produce an appropriate developmental output; although intracellular crosstalk is known to integrate multiple pathways, relatively little is known about extracellular coordination. Methodology/Principal Findings Here, we show that Xenopus Tsukushi (X-TSK), a member of the secreted small leucine rich repeat proteoglycan (SLRP) family, is expressed in ectoderm, endoderm, and the organizer during early development. We have previously reported that X-TSK binds to and inhibits BMP signaling in cooperation with chordin. We now demonstrate two novel interactions: X-TSK binds to and inhibits signaling by FGF8b, in addition to binding to and enhancement of Xnr2 signaling. This signal integration by X-TSK at the extracellular level has an important role in germ layer formation and patterning. Vegetally localized X-TSK potentiates endoderm formation through coordination of BMP, FGF and Xnr2 signaling. In contrast, X-TSK inhibition of FGF-MAPK signaling blocks ventrolateral mesoderm formation, while BMP inhibition enhances organizer formation. These actions of X-TSK are reliant upon its expression in endoderm and dorsal mesoderm, with relative exclusion from ventrolateral mesoderm, in a pattern shaped by FGF signals. Conclusions/Significance Based on our observations, we propose a novel mechanism by which X-TSK refines the field of positional information by integration of multiple pathways in the extracellular space.
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Affiliation(s)
- Samantha A. Morris
- Department of Oncology, The Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom
- * To whom correspondence should be addressed. E-mail: (SM); (SO)
| | - Alexandra D. Almeida
- Department of Oncology, The Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Hideaki Tanaka
- Department of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kunimasa Ohta
- Department of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shin-ichi Ohnuma
- Department of Oncology, The Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom
- * To whom correspondence should be addressed. E-mail: (SM); (SO)
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Kim ES, Moon A. Role of Transforming Growth Factor-β in Tumor Invasion and Metastasis. Toxicol Res 2007. [DOI: 10.5487/tr.2007.23.3.197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Isufi I, Seetharam M, Zhou L, Sohal D, Opalinska J, Pahanish P, Verma A. Transforming Growth Factor-βSignaling in Normal and Malignant Hematopoiesis. J Interferon Cytokine Res 2007; 27:543-52. [PMID: 17651015 DOI: 10.1089/jir.2007.0009] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Transforming growth factor-beta (TGF-beta) is an important physiologic regulator of cell growth and differentiation. TGF-beta has been shown to inhibit the proliferation of quiescent hematopoietic stem cells and stimulate the differentiation of late progenitors to erythroid and myeloid cells. Insensitivity to TGF-beta is implicated in the pathogenesis of many myeloid and lymphoid neoplasms. Loss of extracellular TGF receptors and disruption of intracellular TGF-beta signaling by oncogenes is seen in a variety of malignant and premalignant states. TGF-beta can also affect tumor growth and survival by influencing the secretion of other growth factors and manipulation of the tumor microenvironment. Recent development of small molecule inhibitors of TGF-beta receptors and other signaling intermediaries may allow us to modulate TGF signaling for future therapeutic interventions in cancer.
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Affiliation(s)
- Iris Isufi
- Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Baxter FO, Neoh K, Tevendale MC. The beginning of the end: death signaling in early involution. J Mammary Gland Biol Neoplasia 2007; 12:3-13. [PMID: 17340185 DOI: 10.1007/s10911-007-9033-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Mammary gland involution occurs in two distinct phases: an early, reversible phase, involving extensive apoptosis of the secretory alveolar epithelium without major changes in gland architecture, and a later, irreversible phase, involving remodelling of the gland to its pre-pregnancy state. Multiple signalling pathways are known to be important during early involution, however the precise triggers remain elusive. This review summarizes the roles of a number of key pathways (NF-kappaB, PI(3)K, Stat3, and TGFbeta) in the first phase of involution.
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Affiliation(s)
- Fiona O Baxter
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
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