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Guo S, Ding R, Zhao Q, Wang X, Lv S, Ji XY. Recent Insights into the Roles of PEST-Containing Nuclear Protein. Mol Biotechnol 2025; 67:1800-1813. [PMID: 38762838 DOI: 10.1007/s12033-024-01188-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 04/26/2024] [Indexed: 05/20/2024]
Abstract
PEST-containing nuclear protein (PCNP), a short-lived small nuclear protein with 178 amino acids, is a nuclear protein containing two PEST sequences. PCNP is highly expressed in several malignant tumors such as cervical cancer, rectal cancer, and lung cancer. It is also associated with cell cycle regulation and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and Wnt signaling pathways during tumor growth. The present article discuss how PCNP regulates the PI3K/AKT/mTOR and Wnt signaling pathways and related proteins, and the ubiquitination of PCNP regulates tumor cell cycle as well as the progress of the application of PCNP in the pathophysiology and treatment of colon cancer, human ovarian cancer, thyroid cancer, lung adenocarcinoma and oral squamous cell carcinoma. The main relevant articles were retrieved from PubMed, with keywords such as PEST-containing nuclear protein (PCNP), cancer (tumor), and signaling pathways as inclusion/exclusion criteria. Relevant references has been included and cited in the manuscript.
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Affiliation(s)
- Shiyun Guo
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Ruidong Ding
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Qian Zhao
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Xu Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China
| | - Shuangyu Lv
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China.
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China.
- Kaifeng Key Laboratory for Infectious Diseases and Biosafety, Kaifeng, 475004, Henan, China.
- Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Mazhai, Erqi District, Zhengzhou, 450064, Henan, China.
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2
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Zhang P, Wang Y, Wang Z, Di S, Zhang X, Ma D, Bao Z, Ma F. Chrysanthemum lavandulifolium homolog CYCLIN A2;1 modulates cell division in ray florets. JOURNAL OF EXPERIMENTAL BOTANY 2024; 75:6423-6440. [PMID: 39127875 DOI: 10.1093/jxb/erae325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 08/09/2024] [Indexed: 08/12/2024]
Abstract
The morphology of ray florets in chrysanthemums is tightly associated with cell division and expansion, both of which require proper progression of the cell cycle. Here, we identified a Chrysanthemum lavandulifolium homolog, CYCLIN A2;1 (CYCA2;1), the expression of which in ray florets is negatively correlated with petal width. We found that CYC2a, a TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) transcription factor in the CYCLOIDEA2 (CYC2) family, interacts with and stabilizes CYC2b, and the latter can bind to the promoter of CYCA2;1 to activate its transcription. Overexpression of CYCA2;1 in C. lavandulifolium reduced the size of capitula and ray florets. Cytological analysis revealed that CYCA2;1 overexpression inhibited both cell division and expansion via repression of the mitotic cell cycle in ray florets, the latitudinal development of which was more relatively negatively influenced, thereby leading to increased ratios of petal length to width at later developmental stages. Yeast two-hybrid library screening revealed multiple proteins that interacted with CYCA2;1 including ACTIN-RELATED PROTEIN7 (ARP7), and silencing ARP7 inhibited the development of ray florets. Co-immunoprecipitation assays confirmed that CYCA2;1 could induce the degradation of ARP7 to inhibit the development of ray florets. Taken together, our results indicate the presence of a regulatory network in ray floret development in chrysanthemum consisting of CYC2b-CYCA2;1-ARP7 that acts via governing mitosis. The identification of this network has the potential to facilitate breeding efforts targeted at producing novel ornamental traits in the flowers.
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Affiliation(s)
- Peng Zhang
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
| | - Yahui Wang
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
| | - Zhimin Wang
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
| | - Shengqiang Di
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
| | - Xinyi Zhang
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
| | - Di Ma
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
| | - Zhilong Bao
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
| | - Fangfang Ma
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An, 271018, Shandong, China
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Cheng LH, Wu CC, Wei YH, Wen PJ, Hsu CC, Tsai YC, Wang S. Anti-aging effects of Lacticaseibacillus paracasei PS117 on cognitive and intestinal health in naturally-aged mice: A focus on senescence-related proteins and microbiota composition. Exp Gerontol 2024; 195:112529. [PMID: 39079652 DOI: 10.1016/j.exger.2024.112529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/15/2024] [Accepted: 07/23/2024] [Indexed: 08/03/2024]
Abstract
The rising global aging population underscores the urgency of maintaining the health and well-being of the elderly while reducing the healthcare burden. Anti-aging probiotics have emerged as a promising strategy. This study identified a novel anti-senescence probiotic, Lacticaseibacillus paracasei PS117 (PS117). The effects of PS117 and heat-treated PS117 (HT-PS117) supplementation on cognitive function of naturally-aged male mice were investigated. It was found that PS117 supplementation improved the cognitive performance of aged mice in the Y-maze test. Furthermore, the level of senescence-related protein p16INK4a (p16) were reduced, while anti-senescence protein sirtuin 1 (Sirt1) were increased in the hippocampus. In addition, there was an overall improvement in the intestinal function. Distinct changes in the gut microbiota were also identified, suggesting a potential contribution to the beneficial effects of PS117 supplementation. In conclusion, these results suggest that PS117 supplements could improve cognitive and intestinal functions in naturally-aged mice, while HT-117 improves only intestinal function, possibly by improving the gut microbiota composition.
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Affiliation(s)
- Li-Hao Cheng
- Bened Biomedical Co., Ltd., Taipei 10448, Taiwan, ROC
| | - Chien-Chen Wu
- Bened Biomedical Co., Ltd., Taipei 10448, Taiwan, ROC
| | - Yu-Hsuan Wei
- Bened Biomedical Co., Ltd., Taipei 10448, Taiwan, ROC
| | - Pei-Jun Wen
- Bened Biomedical Co., Ltd., Taipei 10448, Taiwan, ROC
| | | | - Ying-Chieh Tsai
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chial Tung University, Taipei, Taiwan, ROC
| | - Sabrina Wang
- Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
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4
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Zhang J, Zeng X, Guo Q, Sheng Z, Chen Y, Wan S, Zhang L, Zhang P. Small cell lung cancer: emerging subtypes, signaling pathways, and therapeutic vulnerabilities. Exp Hematol Oncol 2024; 13:78. [PMID: 39103941 DOI: 10.1186/s40164-024-00548-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 07/27/2024] [Indexed: 08/07/2024] Open
Abstract
Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by early metastasis, rapid tumor growth and poor prognosis. In recent decades, the epidemiology, initiation and mutation characteristics of SCLC, as well as abnormal signaling pathways contributing to its progression, have been widely studied. Despite extensive investigation, fewer drugs have been approved for SCLC. Recent advancements in multi-omics studies have revealed diverse classifications of SCLC that are featured by distinct characteristics and therapeutic vulnerabilities. With the accumulation of SCLC samples, different subtypes of SCLC and specific treatments for these subtypes were further explored. The identification of different molecular subtypes has opened up novel avenues for the treatment of SCLC; however, the inconsistent and uncertain classification of SCLC has hindered the translation from basic research to clinical applications. Therefore, a comprehensives review is essential to conclude these emerging subtypes and related drugs targeting specific therapeutic vulnerabilities within abnormal signaling pathways. In this current review, we summarized the epidemiology, risk factors, mutation characteristics of and classification, related molecular pathways and treatments for SCLC. We hope that this review will facilitate the translation of molecular subtyping of SCLC from theory to clinical application.
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Affiliation(s)
- Jing Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
| | - Xiaoping Zeng
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Qiji Guo
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Zhenxin Sheng
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Yan Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Shiyue Wan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Lele Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
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Feng Z, Yin J, Zhang Z, Chen Z, Huang L, Tang N, Wang K. O-GlcNAcylation of E3 ubiquitin ligase SKP2 promotes hepatocellular carcinoma proliferation. Oncogene 2024; 43:1149-1159. [PMID: 38396292 DOI: 10.1038/s41388-024-02977-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024]
Abstract
O-linked-β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC.
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Affiliation(s)
- Zhongqi Feng
- Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China
| | - Jiaxin Yin
- Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China
| | - Zhirong Zhang
- Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China
| | - Zhen Chen
- Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China
| | - Luyi Huang
- Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
| | - Ni Tang
- Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
| | - Kai Wang
- Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
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Chan KI, Zhang S, Li G, Xu Y, Cui L, Wang Y, Su H, Tan W, Zhong Z. MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products. Aging Dis 2024; 15:640-697. [PMID: 37450923 PMCID: PMC10917530 DOI: 10.14336/ad.2023.0520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 05/20/2023] [Indexed: 07/18/2023] Open
Abstract
Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC. Animal testing and clinical trials have shown that sustained tumor volume reduction can be achieved when MYC is inactivated, and different combinations of therapeutic agents including MYC inhibitors are currently being developed. In this review, we first provide a summary of the multiple biological functions of the MYC oncoprotein in cancer treatment, highlighting that the equilibrium points of the MYC/MAX, MIZ1/MYC/MAX, and MAD (MNT)/MAX complexes have further potential in cancer treatment that could be used to restrain MYC oncogene expression and its functions in tumorigenesis. We also discuss the multifunctional capacity of MYC in various cellular cancer processes, including its influences on immune response, metabolism, cell cycle, apoptosis, autophagy, pyroptosis, metastasis, angiogenesis, multidrug resistance, and intestinal flora. Moreover, we summarize the MYC therapy patent landscape and emphasize the potential of MYC as a druggable target, using herbal medicine modulators. Finally, we describe pending challenges and future perspectives in biomedical research, involving the development of therapeutic approaches to modulate MYC or its targeted genes. Patients with cancers driven by MYC signaling may benefit from therapies targeting these pathways, which could delay cancerous growth and recover antitumor immune responses.
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Affiliation(s)
- Ka Iong Chan
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Siyuan Zhang
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Guodong Li
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Yida Xu
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Liao Cui
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang 524000, China
| | - Yitao Wang
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Huanxing Su
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
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7
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Opacka A, Żuryń A, Krajewski A, Mikołajczyk K. The role of cyclin Y in normal and pathological cells. Cell Cycle 2023; 22:859-869. [PMID: 36576166 PMCID: PMC10054165 DOI: 10.1080/15384101.2022.2162668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 12/12/2022] [Indexed: 12/29/2022] Open
Abstract
The family protein of cyclins, as well as cyclin-dependent kinases (CDKs) cooperating with them, are broadly researched, as a matter of their dysfunction may lead to tumor transformation. Cyclins are defined as key regulators that have a controlling function of the mammalian nuclear cell divides. Cyclin Y (CCNY) is a recently characterized member of the cyclin family and was first identified from the human testis cDNA library. It is an actin-binding protein acting through decreased actin dynamics at a steady state and during glycine-induced long-term potentiation (LTP) and involves the inhibition of cofilin activation. What is more, CCNY is a positive regulatory subunit of the CDK14/PFTK1 complexes affected by the activation of the Wnt signaling pathway in the G2/M phase by recruiting CDK14/PFTK1 to the plasma membrane and promoting phosphorylation of LRP6. The expression of CCNY has been significantly mentioned within the cell migration and invasion activity both in vivo and in vitro. The aim of this review is evaluation of the expression of CCNY in the physiology processes and compare the expression of this protein in cancer cells, taking into account the impact of the level of expression on tumor progression.
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Affiliation(s)
- Aleksandra Opacka
- Department of Histology and Embryology, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Agnieszka Żuryń
- Department of Histology and Embryology, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Adrian Krajewski
- Department of Histology and Embryology, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Klaudia Mikołajczyk
- Department of Histology and Embryology, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
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8
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Albayrak E, Kocabaş F. Therapeutic targeting and HSC proliferation by small molecules and biologicals. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 135:425-496. [PMID: 37061339 DOI: 10.1016/bs.apcsb.2022.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Hematopoietic stem cells (HSCs) have considerably therapeutic value on autologous and allogeneic transplantation for many malignant/non-malignant hematological diseases, especially with improvement of gene therapy. However, acquirement of limited cell dose from HSC sources is the main handicap for successful transplantation. Therefore, many strategies based on the utilization of various cytokines, interaction of stromal cells, modulation of several extrinsic and intrinsic factors have been developed to promote ex vivo functional HSC expansion with high reconstitution ability until today. Besides all these strategies, small molecules become prominent with their ease of use and various advantages when they are translated to the clinic. In the last two decades, several small molecule compounds have been investigated in pre-clinical studies and, some of them were evaluated in different stages of clinical trials for their safety and efficiencies. In this chapter, we will present an overview of HSC biology, function, regulation and also, pharmacological HSC modulation with small molecules from pre-clinical and clinical perspectives.
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9
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Rawat J, Bhambri A, Pandey U, Banerjee S, Pillai B, Gadgil M. Amino acid abundance and composition in cell culture medium affects trace metal tolerance and cholesterol synthesis. Biotechnol Prog 2023; 39:e3298. [PMID: 36053936 DOI: 10.1002/btpr.3298] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/02/2022] [Accepted: 08/21/2022] [Indexed: 11/05/2022]
Abstract
Amino acid compositions of cell culture media are empirically designed to enhance cell growth and productivity and vary both across media formulations and over the course of culture due to imbalance in supply and consumption. The interconnected nature of the amino acid transporters and metabolism suggests that changes in amino acid composition can affect cell physiology. In this study, we explore the effect of a step change in amino acid composition from a DMEM: F12-based medium to a formulation varying in relative abundances of all amino acids, evaluated at two amino acid concentrations (lean LAA vs. rich HAA). Cell growth was inhibited in LAA but not HAA. In addition to the expected effects on expression of the cell cycle, amino acid response and mTOR pathway genes in LAA, we observed an unanticipated effect on zinc uptake and efflux genes. This was accompanied by a lower tolerance to zinc supplementation in LAA but not in the other formulations. Histidine was sufficient but not necessary to prevent such zinc toxicity. Additionally, an unanticipated downregulation of genes in the cholesterol synthesis pathway was observed in HAA, accompanied by an increase in cellular cholesterol content, which may depend on the relative abundances of glutamine and other amino acids. This study shows that changes in the amino acid composition without any evident effect on growth may have profound effects on metabolism. Such analyses can help rationalize the designing of medium and feed formulations for bioprocess applications beyond replenishment of consumed components.
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Affiliation(s)
- Jyoti Rawat
- Chemical Engineering and Process Development, CSIR-National Chemical Laboratory, Pune, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory Campus, Ghaziabad, India
| | - Aksheev Bhambri
- Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory Campus, Ghaziabad, India.,Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi, India
| | - Ujjiti Pandey
- Chemical Engineering and Process Development, CSIR-National Chemical Laboratory, Pune, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory Campus, Ghaziabad, India
| | - Sanchita Banerjee
- Chemical Engineering and Process Development, CSIR-National Chemical Laboratory, Pune, India
| | - Beena Pillai
- Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi, India
| | - Mugdha Gadgil
- Chemical Engineering and Process Development, CSIR-National Chemical Laboratory, Pune, India.,Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory Campus, Ghaziabad, India
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10
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Sund DT, Brouwer AF, Walline HM, Carey TE, Meza R, Jackson T, Eisenberg MC. Understanding the mechanisms of HPV-related carcinogenesis: Implications for cell cycle dynamics. J Theor Biol 2022; 551-552:111235. [PMID: 35973606 PMCID: PMC9838640 DOI: 10.1016/j.jtbi.2022.111235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 05/07/2022] [Accepted: 07/26/2022] [Indexed: 01/17/2023]
Abstract
The role of human papillomavirus (HPV) as a causative agent for epithelial cancers is well-known, but many open questions remain regarding the downstream gene regulatory effects of viral proteins E6 and E7 on the cell cycle. Here, we extend a cell cycle model originally presented by Gérard and Goldbeter (2009) in order to capture the effects of E6 and E7 on key actors in the cell cycle. Results suggest that E6 is sufficient to reverse p53-induced quiescence, while E7 is sufficient to reverse p16INK4a-induced quiescence; both E6 and E7 are necessary when p53 and p16INK4a are both active. Moreover, E7 appears to play a role as a "growth factor substitute", inducing cell division in the absence of growth factor. Low levels of E7 may permit regular cell division, but the results suggest that higher levels of E7 dysregulate the cell cycle in ways that may destabilize the cellular genome. The mechanisms explored here provide opportunities for developing new treatment targets that take advantage of the cell cycle regulatory system to prevent HPV-related cancer effects.
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Affiliation(s)
- Derrick T Sund
- Department of Mathematics, University of Michigan, Ann Arbor, MI, United States.
| | - Andrew F Brouwer
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
| | - Heather M Walline
- Department of Otolaryngology, University of Michigan, Ann Arbor, MI, United States
| | - Thomas E Carey
- Department of Otolaryngology, University of Michigan, Ann Arbor, MI, United States
| | - Rafael Meza
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
| | - Trachette Jackson
- Department of Mathematics, University of Michigan, Ann Arbor, MI, United States
| | - Marisa C Eisenberg
- Department of Mathematics, University of Michigan, Ann Arbor, MI, United States; Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States.
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11
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Genome-Wide Identification, Expression Profiling, and Characterization of Cyclin-like Genes Reveal Their Role in the Fertility of the Diamondback Moth. BIOLOGY 2022; 11:biology11101493. [PMID: 36290396 PMCID: PMC9598266 DOI: 10.3390/biology11101493] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 11/07/2022]
Abstract
Simple Summary Cyclin genes are known as cell cycle regulators and play a significant role in the fertility of different organisms, including mice and insects. Until now, no study has been performed on the complete identification of the cyclin genes in insects. Here, we identified 21 cyclin genes in the diamondback moth (DBM) genome through a comprehensive genome-wide analysis and evaluated the gene structure, genomic location, and evolutionary relationship. Cis-regulatory elements and potential miRNA targeting the cyclin genes were also assessed. By analyzing the transcriptomic and RT-qPCR based expression profiling at different stages and tissues, we found that the majority of the cyclin genes were significantly expressed in the reproductive tissues. Moreover, RNAi-mediated characterization of PxCyc B1 showed its role in female fertility. The current study provides a basis for further evaluation of the cyclin genes, which may be used as a potential target for pest management programs. Abstract Cyclin-like genes are primarily considered as cell cycle regulators and have shown to be crucial for insect growth, development, reproduction, and fertility. However, no research has been performed on the cyclin-like genes in the diamondback moth (Plutella xylostella). Here, we identified the 21 cyclin genes in the genome of P. xylostella and clustered them into four groups. Most cyclin genes showed a well-maintained gene structure and motif distribution within the same group. The putative promoter regions of cyclin genes contained several transcription binding factors related to reproduction, along with growth and development. Furthermore, 16 miRNAs were identified targeting the 13 cyclin genes. Transcriptome and quantitative real-time PCR (qRT-PCR)-based expression profiling of cyclin-like genes at different stages and tissues were evaluated, revealing that 16 out of 21 cyclin genes were highly expressed in reproductive tissues of adult females and males. The Cyclin B1 gene (PxCyc B1) was only expressed in the ovary of the adult female and selected for the subsequent analysis. RNAi-mediated suppression of PxCyc B1 interrupted the external genitalia and length of the ovariole of female adults. Furthermore, the egg-laying capacity and hatching rate were also significantly decreased by suppressing the PxCyc B1, indicating the importance of cyclin genes in the reproduction and fertility of P. xylostella. The current study explained the detailed genome-wide analysis of cyclin-like genes in P. xylostella, which provided a basis for subsequent research to assess the roles of cyclin genes in reproduction, and the cyclin gene may be considered an effective target site to control this pest.
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Expression patterns and therapeutic implications of CDK4 across multiple carcinomas: a molecular docking and MD simulation study. Med Oncol 2022; 39:158. [DOI: 10.1007/s12032-022-01779-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/20/2022] [Indexed: 10/16/2022]
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Clostridium novyi’s Alpha-Toxin Changes Proteome and Phosphoproteome of HEp-2 Cells. Int J Mol Sci 2022; 23:ijms23179939. [PMID: 36077344 PMCID: PMC9456407 DOI: 10.3390/ijms23179939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/17/2022] [Accepted: 08/27/2022] [Indexed: 11/16/2022] Open
Abstract
C. novyi type A produces the alpha-toxin (TcnA) that belongs to the large clostridial glucosylating toxins (LCGTs) and is able to modify small GTPases by N-acetylglucosamination on conserved threonine residues. In contrast, other LCGTs including Clostridioides difficile toxin A and toxin B (TcdA; TcdB) modify small GTPases by mono-o-glucosylation. Both modifications inactivate the GTPases and cause strong effects on GTPase-dependent signal transduction pathways and the consequent reorganization of the actin cytoskeleton leading to cell rounding and finally cell death. However, the effect of TcnA on target cells is largely unexplored. Therefore, we performed a comprehensive screening approach of TcnA treated HEp-2 cells and analyzed their proteome and their phosphoproteome using LC-MS-based methods. With this data-dependent acquisition (DDA) approach, 5086 proteins and 9427 phosphosites could be identified and quantified. Of these, 35 proteins were found to be significantly altered after toxin treatment, and 1832 phosphosites were responsive to TcnA treatment. By analyzing the TcnA-induced proteomic effects of HEp-2 cells, 23 common signaling pathways were identified to be altered, including Actin Cytoskeleton Signaling, Epithelial Adherens Junction Signaling, and Signaling by Rho Family GTPases. All these pathways are also regulated after application of TcdA or TcdB of C. difficile. After TcnA treatment the regulation on phosphorylation level was much stronger compared to the proteome level, in terms of both strength of regulation and the number of regulated phosphosites. Interestingly, various signaling pathways such as Signaling by Rho Family GTPases or Integrin Signaling were activated on proteome level while being inhibited on phosphorylation level or vice versa as observed for the Role of BRCA1 in DNA Damage Response. ZIP kinase, as well as Calmodulin-dependent protein kinases IV & II, were observed as activated while Aurora-A kinase and CDK kinases tended to be inhibited in cells treated with TcnA based on their substrate regulation pattern.
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Singh G, Storey KB. Regulation of the cell cycle under anoxia stress in tail muscle and hepatopancreas of the freshwater crayfish, Orconectes virilis. Comp Biochem Physiol A Mol Integr Physiol 2022; 269:111215. [PMID: 35429664 DOI: 10.1016/j.cbpa.2022.111215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/09/2022] [Accepted: 04/10/2022] [Indexed: 10/18/2022]
Abstract
Regulation of the cell cycle is an understudied response to oxygen deprivation among crustaceans. The virile crayfish, Orconectes virilis, is a freshwater crustacean that when challenged by environmental oxygen limitation undergoes metabolic rate depression (to ~30% of normal levels) and switches to anaerobic metabolism to generate energy. To understand how crayfish regulate the cell cycle in response to anoxia, key proteins involved in cell cycle control were analyzed in muscle and hepatopancreas. At the G1/S barrier, an overall upregulation of positive regulators of cell cycle progression was indicated by the responses of G1 cyclins (cyclin D and cyclin E) and Cyclin dependent kinases (CDK4, CDK6 and CDK2) under anoxia. Although the levels of Cyclin kinase inhibitors (CKIs) at this juncture were also upregulated (P15/16 and P21 (T145) in muscle and P16 (S152) in hepatopancreas), levels of a major regulator of this phase and driver to S-phase, E2F1, were significantly higher in both tissues in conjunction with deactivation of its inhibitor, Retinoblastoma (Rb) protein. At the G2/M barrier, expression profiles of the G2 cyclin B suggested cell cycle progression despite overall trend of higher activities of checkpoint kinases, (Chk1 (S317) and Chk2 (S19)), that also negatively regulate the cyclin B-CDK1 complex via CdC25C (cell division cycle 25) whose levels remained unchanged. Overall, the present study suggests continued cell cycle progression, albeit with potential deceleration, as indicated by checkpoint kinases and kinase inhibitor profiles that might play a role in protecting tissues from apoptotic damage under chronic anoxic stress.
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Affiliation(s)
- Gurjit Singh
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada. https://twitter.com/GurjitS92273426
| | - Kenneth B Storey
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
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Morris MC. A Toolbox of Fluorescent Peptide Biosensors to Highlight Protein Kinases in Complex Samples : focus on cyclin‐dependent kinases. European J Org Chem 2022. [DOI: 10.1002/ejoc.202200120] [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]
Affiliation(s)
- May Catherine Morris
- IBMM-UMR5247 Peptide & Proteins Faculté de Pharmacie,15 Av. Charles Flahault 34093 Montpellier FRANCE
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Shining Light on Protein Kinase Biomarkers with Fluorescent Peptide Biosensors. Life (Basel) 2022; 12:life12040516. [PMID: 35455007 PMCID: PMC9026840 DOI: 10.3390/life12040516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/21/2022] [Accepted: 03/28/2022] [Indexed: 11/23/2022] Open
Abstract
Protein kinases (PKs) are established gameplayers in biological signalling pathways, and a large body of evidence points to their dysregulation in diseases, in particular cancer, where rewiring of PK networks occurs frequently. Fluorescent biosensors constitute attractive tools for probing biomolecules and monitoring dynamic processes in complex samples. A wide variety of genetically encoded and synthetic biosensors have been tailored to report on PK activities over the last decade, enabling interrogation of their function and insight into their behaviour in physiopathological settings. These optical tools can further be used to highlight enzymatic alterations associated with the disease, thereby providing precious functional information which cannot be obtained through conventional genetic, transcriptomic or proteomic approaches. This review focuses on fluorescent peptide biosensors, recent developments and strategies that make them attractive tools to profile PK activities for biomedical and diagnostic purposes, as well as insights into the challenges and opportunities brought by this unique toolbox of chemical probes.
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Cyclin-dependent Kinases 4/6 Inhibitors in Neuroendocrine Neoplasms: from Bench to Bedside. Curr Oncol Rep 2022; 24:715-722. [PMID: 35262877 DOI: 10.1007/s11912-022-01251-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2021] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Cyclin-dependent kinases (CDKs) are key regulators that play an important role in cell division. Palbociclib, ribociclib and abemaciclib showed significant antitumor activity in several malignancies and, recently, also a myeloprotective effect for trilaciclib when added to chemotherapy. The purpose of this review is to highlight the current evidence for CDK4/6 inhibitors in neuroendocrine neoplasms (NENs). RECENT FINDINGS Preclinical results showed a promising antitumor activity of CDK4/6 inhibitors in neuroendocrine tumors (NETs), but so far, the very few small clinical trials did not show a strong impact on progression free survival (PFS) and objective response in NETs. Meanwhile, the CDK4/6 inhibitor trilaciclib revealed significant effects in reducing chemotherapy-induced myelosuppression in small cell lung cancer (SCLC). Up to date, CDK4/6 inhibitors are still considered investigational in NETs as antitumor agents, whereas trilaciclib can be used in the routine clinical practice in extensive stage SCLC patients for reducing myelotoxicity of standard chemotherapy.
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Bailey T, Nieto A, McDonald P. Inhibition of the Monocarboxylate Transporter 1 (MCT1) Promotes 3T3-L1 Adipocyte Proliferation and Enhances Insulin Sensitivity. Int J Mol Sci 2022; 23:ijms23031901. [PMID: 35163825 PMCID: PMC8836706 DOI: 10.3390/ijms23031901] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 01/17/2022] [Accepted: 01/31/2022] [Indexed: 11/16/2022] Open
Abstract
Enlarged, hypertrophic adipocytes are less responsive to insulin and are a hallmark feature of obesity, contributing to many of the negative metabolic consequences of excess adipose tissue. Although the mechanisms remain unclear, the adipocyte size appears to be inversely correlated with insulin sensitivity and glucose tolerance, wherein smaller adipocytes are insulin-sensitive and larger adipocytes develop insulin resistance and exhibit an impaired glucose uptake. Thus, pharmacological strategies aimed at regulating adipocyte hypertrophy (increase in adipocyte size) in favor of promoting hyperplasia (increase in adipocyte number) have the potential to improve adipocyte insulin sensitivity and provide therapeutic benefits in the context of metabolic disorders. As white adipose tissue can metabolize large amounts of glucose to lactate, using transcriptomics and in vitro characterization we explore the functional consequences of inhibiting monocarboxylate transporter 1 (MCT1) activity in fully differentiated adipocytes. Our studies show that the pharmacological inhibition of MCT1, a key regulator of the cellular metabolism and proliferation, promotes the re-entry of mature adipocytes into the cell cycle. Furthermore, we demonstrate that inhibitor-treated adipocytes exhibit an enhanced insulin-stimulated glucose uptake as compared with untreated adipocytes, and that this outcome is dependent on the cyclin-dependent kinase 1 (CDK1) activity. In summary, we identify a mechanism though which MCT1 inhibition improves the insulin sensitivity of mature adipocytes by inducing cell cycle re-entry. These results provide the foundation for future studies investigating the role MCT1 plays in adipocyte hyperplasia, and its therapeutic potential as a drug target for obesity and metabolic disease.
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Affiliation(s)
- Tracey Bailey
- Department of Cancer Physiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA;
| | - Ainhoa Nieto
- Primary Pharmacology Group, Discovery Sciences, Pfizer, Inc., 445 Eastern Point Rd, Groton, CT 06340, USA;
| | - Patricia McDonald
- Department of Cancer Physiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA;
- Correspondence: ; Tel.: +1-813-745-6684
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Xu YC, Liu GH, Xu YH, Zhao T, Zheng H, Tan XY. Physiological and transcriptomic analyses reveal the toxicological mechanism and risk assessment of environmentally-relevant waterborne tetracycline exposure on the gills of tilapia (Oreochromis niloticus). THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 806:151290. [PMID: 34743874 DOI: 10.1016/j.scitotenv.2021.151290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/06/2021] [Accepted: 10/24/2021] [Indexed: 06/13/2023]
Abstract
With the increasing application of tetracycline (TC) in medical treatment, animal husbandry and aquaculture in recent decades, high quantities of TC have been frequently detected in the aquatic environment, and accordingly TC-related toxicity and environmental pollution have become a global concern. The present study was performed to explore the toxicological influences of TC exposure at its environmentally relevant concentrations on the gills of tilapia Oreochromis niloticus, based on the alteration in histopathology, oxidative stress, inflammatory response, cell cycle, mitochondrial function, apoptosis, and transcriptomic analysis. Our findings revealed that TC exposure damaged the structure and function, induced oxidative stress, affected inflammatory responses, and reduced Na+/K+-ATPase (NKA) activity in the gills. TC also caused the inhibition in cell cycle, resulted in mitochondrial dysfunction and activated apoptosis. Further transcriptomic analysis indicated the extensive influences of TC exposure on the gill function, and immune system was the main target to waterborne TC exposure. These results elucidated that environmental TC had more complex toxicological effects on gills of fish than previously assessed, and provided novel insight into molecular toxicology of TC on fish and good basis for assessing the environmental risk of TC.
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Affiliation(s)
- Yi-Chuang Xu
- Laboratory of Molecular Nutrition and Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Guang-Hui Liu
- Laboratory of Molecular Nutrition and Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Yi-Huan Xu
- Laboratory of Molecular Nutrition and Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Tao Zhao
- Laboratory of Molecular Nutrition and Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Hua Zheng
- Laboratory of Molecular Nutrition and Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiao-Ying Tan
- Laboratory of Molecular Nutrition and Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan 430070, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
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Hypoxia-induced RBBP7 promotes esophagus cancer progression by inducing CDK4 expression. Acta Biochim Biophys Sin (Shanghai) 2022; 54:179-186. [PMID: 35538026 PMCID: PMC9909297 DOI: 10.3724/abbs.2021027] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hypoxia-induced epigenetic regulation calls for more effective therapeutic targets for esophageal cancer. We used GEPIA and UALCAN databases to screen survival-related and cancer stage-associated genes. Eca109 and KYSE450 esophageal cancer cell lines were cultured under normoxia, hypoxia, or CoCl-induced hypoxia conditions, which were further transfected with plasmids expressing RB binding protein 7 (RBBP7), hypoxia-inducible factor 1 (HIF1)-α, or RBBP7 shRNA. Colony formation and MTT assays were used to detect cell proliferation. Tumor sphere formation and stemness marker detection were applied to assess cell stemness. RT-PCR and western blot analysis were used to detect the relative mRNA level and protein expression, respectively. Luciferase assay was utilized to detect the direct interaction between HIF1α and RBBP7. Up-regulated RBBP7 was identified as one of the most prominent survival-related genes, which is negatively correlated with the overall survival (OS), disease recurrence-free survival (DFS), and tumor stages. Hypoxia-induced HIF1α up-regulates RBBP7 expression, which promotes esophagus cancer cell viability, proliferation, and stemness with increased cyclin-dependent kinase 4 (CDK4) expression. Luciferase reporter assay verified that HIF1α transcriptionally regulates the expression of RBBP7. We conclude that hypoxia induces high expression of RBBP7 which is at least partially mediated by HIF1α, up-regulates the expression of downstream CDK4, and thereby promotes tumor progression in esophageal cancer cells.
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21
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A Decade of Pollen Phosphoproteomics. Int J Mol Sci 2021; 22:ijms222212212. [PMID: 34830092 PMCID: PMC8619407 DOI: 10.3390/ijms222212212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/01/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Angiosperm mature pollen represents a quiescent stage with a desiccated cytoplasm surrounded by a tough cell wall, which is resistant to the suboptimal environmental conditions and carries the genetic information in an intact stage to the female gametophyte. Post pollination, pollen grains are rehydrated, activated, and a rapid pollen tube growth starts, which is accompanied by a notable metabolic activity, synthesis of novel proteins, and a mutual communication with female reproductive tissues. Several angiosperm species (Arabidopsis thaliana, tobacco, maize, and kiwifruit) were subjected to phosphoproteomic studies of their male gametophyte developmental stages, mostly mature pollen grains. The aim of this review is to compare the available phosphoproteomic studies and to highlight the common phosphoproteins and regulatory trends in the studied species. Moreover, the pollen phosphoproteome was compared with root hair phosphoproteome to pinpoint the common proteins taking part in their tip growth, which share the same cellular mechanisms.
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Lee SM, Kaye KM, Slack FJ. Cellular microRNA-127-3p suppresses oncogenic herpesvirus-induced transformation and tumorigenesis via down-regulation of SKP2. Proc Natl Acad Sci U S A 2021; 118:e2105428118. [PMID: 34725152 PMCID: PMC8609319 DOI: 10.1073/pnas.2105428118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) causes the endothelial tumor KS, a leading cause of morbidity and mortality in sub-Saharan Africa. KSHV-encoded microRNAs (miRNAs) are known to play an important role in viral oncogenesis; however, the role of host miRNAs in KS tumorigenesis remains largely unknown. Here, high-throughput small-RNA sequencing of the cellular transcriptome in a KS xenograft model revealed miR-127-3p as one of the most significantly down-regulated miRNAs, which we validated in KS patient tissues. We show that restoration of miR-127-3p suppresses KSHV-driven cellular transformation and proliferation and induces G1 cell cycle arrest by directly targeting the oncogene SKP2. This miR-127-3p-induced G1 arrest is rescued by disrupting the miR-127-3p target site in SKP2 messenger RNA (mRNA) using gene editing. Mechanistically, miR-127-3p-mediated SKP2 repression elevates cyclin-dependent kinase (CDK) inhibitor p21Cip1 and down-regulates cyclin E, cyclin A, and CDK2, leading to activation of the RB protein tumor suppressor pathway and suppression of the transcriptional activities of E2F and Myc, key oncoprotein transcription factors crucial for KSHV tumorigenesis. Consequently, metabolomics analysis during miR-127-3p-induced cell cycle arrest revealed significant depletion of dNTP pools, consistent with RB-mediated repression of key dNTP biosynthesis enzymes. Furthermore, miR-127-3p reconstitution in a KS xenograft mouse model suppresses KSHV-positive tumor growth by targeting SKP2 in vivo. These findings identify a previously unrecognized tumor suppressor function for miR-127-3p in KS and demonstrate that the miR-127-3p/SKP2 axis is a viable therapeutic strategy for KS.
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Affiliation(s)
- Soo Mi Lee
- Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
- Program in Virology, Division of Medical Sciences, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138
| | - Kenneth M Kaye
- Program in Virology, Division of Medical Sciences, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Frank J Slack
- Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
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Homayoonfal M, Asemi Z, Yousefi B. Targeting microRNAs with thymoquinone: a new approach for cancer therapy. Cell Mol Biol Lett 2021; 26:43. [PMID: 34627167 PMCID: PMC8502376 DOI: 10.1186/s11658-021-00286-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/27/2021] [Indexed: 02/08/2023] Open
Abstract
Cancer is a global disease involving transformation of normal cells into tumor types via numerous mechanisms, with mortality among all generations, in spite of the breakthroughs in chemotherapy, radiotherapy and/or surgery for cancer treatment. Since one in six deaths is due to cancer, it is one of the overriding priorities of world health. Recently, bioactive natural compounds have been widely recognized due to their therapeutic effects for treatment of various chronic disorders, notably cancer. Thymoquinone (TQ), the most valuable constituent of black cumin seeds, has shown anti-cancer characteristics in a wide range of animal models. The revolutionary findings have revealed TQ's ability to regulate microRNA (miRNA) expression, offering a promising approach for cancer therapy. MiRNAs are small noncoding RNAs that modulate gene expression by means of variation in features of mRNA. MiRNAs manage several biological processes including gene expression and cellular signaling pathways. Accordingly, miRNAs can be considered as hallmarks for cancer diagnosis, prognosis and therapy. The purpose of this study was to review the various molecular mechanisms by which TQ exerts its potential as an anti-cancer agent through modulating miRNAs.
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Affiliation(s)
- Mina Homayoonfal
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Ahmadi SE, Rahimi S, Zarandi B, Chegeni R, Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. J Hematol Oncol 2021; 14:121. [PMID: 34372899 PMCID: PMC8351444 DOI: 10.1186/s13045-021-01111-4] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/12/2021] [Indexed: 12/17/2022] Open
Abstract
MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.
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Affiliation(s)
- Seyed Esmaeil Ahmadi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Rahimi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahman Zarandi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rouzbeh Chegeni
- Medical Laboratory Sciences Program, College of Health and Human Sciences, Northern Illinois University, DeKalb, IL, USA.
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Integrative Functional Genomic Analysis of Molecular Signatures and Mechanistic Pathways in the Cell Cycle Underlying Alzheimer's Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5552623. [PMID: 34336099 PMCID: PMC8290224 DOI: 10.1155/2021/5552623] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 06/25/2021] [Indexed: 11/18/2022]
Abstract
Objective Alzheimer's disease (AD) is associated with cell cycle reentry of mature neurons that subsequently undergo degeneration. This study is aimed to identify key regulators of the cell cycle and their underlying pathways for developing optimal treatment of AD. Methods RNA sequencing data were profiled to screen for differentially expressed genes in the cell cycle. Correlation of created modules with AD phenotype was computed by weight gene correlation network analysis (WGCNA). Signature genes for trophic factor receptors were determined using Pearson correlation coefficient (PCC) analysis. Results Among the 13,679 background genes, 775 cell cycle genes and 77 trophic factor receptors were differentially expressed in AD versus nondementia controls. Four coexpression modules were constructed by WGCNA, among which the turquoise module had the strongest correlation with AD. According to PCC analysis, 10 signature trophic receptors most strongly interacting with cell cycle genes were filtered and subsequently displayed in the global regulatory network. Further cross-talking pathways of signature receptors, such as glutamatergic synapse, long-term potentiation, PI3K-Akt, and MAPK signaling pathways, were identified. Conclusions Our findings highlighted the mechanistic pathways of signature trophic receptors in cell cycle perturbation underlying AD pathogenesis, thereby providing new molecular targets for therapeutic intervention in AD.
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Barberis M. Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER. NPJ Syst Biol Appl 2021; 7:28. [PMID: 34117265 PMCID: PMC8196193 DOI: 10.1038/s41540-021-00187-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/07/2021] [Indexed: 12/20/2022] Open
Abstract
In budding yeast, synchronization of waves of mitotic cyclins that activate the Cdk1 kinase occur through Forkhead transcription factors. These molecules act as controllers of their sequential order and may account for the separation in time of incompatible processes. Here, a Forkhead-mediated design principle underlying the quantitative model of Cdk control is proposed for budding yeast. This design rationalizes timing of cell division, through progressive and coordinated cyclin/Cdk-mediated phosphorylation of Forkhead, and autonomous cyclin/Cdk oscillations. A "clock unit" incorporating this design that regulates timing of cell division is proposed for both yeast and mammals, and has a DRIVER operating the incompatible processes that is instructed by multiple CLOCKS. TIMERS determine whether the clocks are active, whereas CONTROLLERS determine how quickly the clocks shall function depending on external MODULATORS. This "clock unit" may coordinate temporal waves of cyclin/Cdk concentration/activity in the eukaryotic cell cycle making the driver operate the incompatible processes, at separate times.
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Affiliation(s)
- Matteo Barberis
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford, UK.
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
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Sesquiterpene lactones of Aucklandia lappa: Pharmacology, pharmacokinetics, toxicity, and structure–activity relationship. CHINESE HERBAL MEDICINES 2021; 13:167-176. [PMID: 36117502 PMCID: PMC9476744 DOI: 10.1016/j.chmed.2020.11.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/28/2020] [Accepted: 11/29/2020] [Indexed: 12/12/2022] Open
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Kyselova A, Siragusa M, Anthes J, Solari FA, Loroch S, Zahedi RP, Walter U, Fleming I, Randriamboavonjy V. Cyclin Y is expressed in Platelets and Modulates Integrin Outside-in Signaling. Int J Mol Sci 2020; 21:ijms21218239. [PMID: 33153214 PMCID: PMC7662234 DOI: 10.3390/ijms21218239] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/26/2020] [Accepted: 11/01/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetes is associated with platelet hyper-reactivity and enhanced risk of thrombosis development. Here we compared protein expression in platelets from healthy donors and diabetic patients to identify differentially expressed proteins and their possible function in platelet activation. Mass spectrometry analyses identified cyclin Y (CCNY) in platelets and its reduced expression in platelets from diabetic patients, a phenomenon that could be attributed to the increased activity of calpains. To determine the role of CCNY in platelets, mice globally lacking the protein were studied. CCNY-/- mice demonstrated lower numbers of circulating platelets but platelet responsiveness to thrombin and a thromboxane A2 analogue were comparable with that of wild-type mice, as was agonist-induced α and dense granule secretion. CCNY-deficient platelets demonstrated enhanced adhesion to fibronectin and collagen as well as an attenuated spreading and clot retraction, indicating an alteration in "outside in" integrin signalling. This phenotype was accompanied by a significant reduction in the agonist-induced tyrosine phosphorylation of β3 integrin. Taken together we have shown that CCNY is present in anucleated platelets where it is involved in the regulation of integrin-mediated outside in signalling associated with thrombin stimulation.
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Affiliation(s)
- Anastasia Kyselova
- Institute for Vascular Signaling, Centre of Molecular Medicine, Goethe University, Frankfurt am Main, 60590 Frankfurt, Germany; (A.K.); (M.S.); (J.A.); (I.F.)
- German Center of Cardiovascular Research (DZHK), Partner site Rhein Main, 17475 Greifswald, Germany; (S.L.); (R.P.Z.); (U.W.)
| | - Mauro Siragusa
- Institute for Vascular Signaling, Centre of Molecular Medicine, Goethe University, Frankfurt am Main, 60590 Frankfurt, Germany; (A.K.); (M.S.); (J.A.); (I.F.)
- German Center of Cardiovascular Research (DZHK), Partner site Rhein Main, 17475 Greifswald, Germany; (S.L.); (R.P.Z.); (U.W.)
| | - Julian Anthes
- Institute for Vascular Signaling, Centre of Molecular Medicine, Goethe University, Frankfurt am Main, 60590 Frankfurt, Germany; (A.K.); (M.S.); (J.A.); (I.F.)
| | - Fiorella Andrea Solari
- Leibniz–Institute for Analytical Sciences (ISAS)- e.V., Otto-Hahn-Str. 6b, 44227 Dortmund, Germany;
| | - Stefan Loroch
- German Center of Cardiovascular Research (DZHK), Partner site Rhein Main, 17475 Greifswald, Germany; (S.L.); (R.P.Z.); (U.W.)
- Leibniz–Institute for Analytical Sciences (ISAS)- e.V., Otto-Hahn-Str. 6b, 44227 Dortmund, Germany;
| | - René P. Zahedi
- German Center of Cardiovascular Research (DZHK), Partner site Rhein Main, 17475 Greifswald, Germany; (S.L.); (R.P.Z.); (U.W.)
- Leibniz–Institute for Analytical Sciences (ISAS)- e.V., Otto-Hahn-Str. 6b, 44227 Dortmund, Germany;
| | - Ulrich Walter
- German Center of Cardiovascular Research (DZHK), Partner site Rhein Main, 17475 Greifswald, Germany; (S.L.); (R.P.Z.); (U.W.)
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, 55131 Mainz, Germany
| | - Ingrid Fleming
- Institute for Vascular Signaling, Centre of Molecular Medicine, Goethe University, Frankfurt am Main, 60590 Frankfurt, Germany; (A.K.); (M.S.); (J.A.); (I.F.)
- German Center of Cardiovascular Research (DZHK), Partner site Rhein Main, 17475 Greifswald, Germany; (S.L.); (R.P.Z.); (U.W.)
| | - Voahanginirina Randriamboavonjy
- Institute for Vascular Signaling, Centre of Molecular Medicine, Goethe University, Frankfurt am Main, 60590 Frankfurt, Germany; (A.K.); (M.S.); (J.A.); (I.F.)
- German Center of Cardiovascular Research (DZHK), Partner site Rhein Main, 17475 Greifswald, Germany; (S.L.); (R.P.Z.); (U.W.)
- Correspondence: ; Tel.: +49-69-6301-6973; Fax: +49-69-6301-86880
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Dang F, Nie L, Wei W. Ubiquitin signaling in cell cycle control and tumorigenesis. Cell Death Differ 2020; 28:427-438. [PMID: 33130827 PMCID: PMC7862229 DOI: 10.1038/s41418-020-00648-0] [Citation(s) in RCA: 207] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
Cell cycle progression is a tightly regulated process by which DNA replicates and cell reproduces. The major driving force underlying cell cycle progression is the sequential activation of cyclin-dependent kinases (CDKs), which is achieved in part by the ubiquitin-mediated proteolysis of their cyclin partners and kinase inhibitors (CKIs). In eukaryotic cells, two families of E3 ubiquitin ligases, anaphase-promoting complex/cyclosome and Skp1-Cul1-F-box protein complex, are responsible for ubiquitination and proteasomal degradation of many of these CDK regulators, ensuring cell cycle progresses in a timely and precisely regulated manner. In the past couple of decades, accumulating evidence have demonstrated that the dysregulated cell cycle transition caused by inefficient proteolytic control leads to uncontrolled cell proliferation and finally results in tumorigenesis. Based upon this notion, targeting the E3 ubiquitin ligases involved in cell cycle regulation is expected to provide novel therapeutic strategies for cancer treatment. Thus, a better understanding of the diversity and complexity of ubiquitin signaling in cell cycle regulation will shed new light on the precise control of the cell cycle progression and guide anticancer drug development. ![]()
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Affiliation(s)
- Fabin Dang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Li Nie
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,State Key Laboratory for Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
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Titus AS, V H, Kailasam S. Coordinated regulation of cell survival and cell cycle pathways by DDR2-dependent SRF transcription factor in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 2020; 318:H1538-H1558. [PMID: 32412792 DOI: 10.1152/ajpheart.00740.2019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Relative resistance to apoptosis and the ability to proliferate and produce a collagen-rich scar determine the critical role of cardiac fibroblasts in wound healing and tissue remodeling following myocardial injury. Identification of cardiac fibroblast-specific factors and mechanisms underlying these aspects of cardiac fibroblast function is therefore of considerable scientific and clinical interest. In the present study, gene knockdown and overexpression approaches and promoter binding assays showed that discoidin domain receptor 2 (DDR2), a mesenchymal cell-specific collagen receptor tyrosine kinase localized predominantly in fibroblasts in the heart, acts via ERK1/2 MAPK-activated serum response factor (SRF) transcription factor to enhance the expression of antiapoptotic cIAP2 in cardiac fibroblasts, conferring resistance against oxidative injury. Furthermore, DDR2 was found to act via ERK1/2 MAPK-activated SRF to transcriptionally upregulate Skp2 that in turn facilitated post-translational degradation of p27, the cyclin-dependent kinase inhibitor that causes cell cycle arrest, to promote G1-S transition, as evidenced by Rb phosphorylation, increased proliferating cell nuclear antigen (PCNA) levels, and flow cytometry. DDR2-dependent ERK1/2 MAPK activation also suppressed forkhead box O 3a (FoxO3a)-mediated transcriptional induction of p27. Inhibition of the binding of collagen type I to DDR2 using WRG-28 indicated the obligate role of collagen type I in the activation of DDR2 and its regulatory role in cell survival and cell cycle protein expression. Notably, DDR2 levels positively correlated with SRF, cIAP2, and PCNA levels in cardiac fibroblasts from spontaneously hypertensive rats. To conclude, DDR2-mediated ERK1/2 MAPK activation facilitates coordinated regulation of cell survival and cell cycle progression in cardiac fibroblasts via SRF.NEW & NOTEWORTHY Relative resistance to apoptosis and the ability to proliferate and produce a collagen-rich scar enable cardiac fibroblasts to play a central role in myocardial response to injury. This study reports novel findings that mitogen-stimulated cardiac fibroblasts exploit a common regulatory mechanism involving collagen receptor (DDR2)-dependent activation of ERK1/2 MAPK and serum response factor to achieve coordinated regulation of apoptosis resistance and cell cycle progression, which could facilitate their survival and function in the injured myocardium.
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Affiliation(s)
- Allen Sam Titus
- Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
| | - Harikrishnan V
- Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
| | - Shivakumar Kailasam
- Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
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Khazaaleh M, Samarasinghe S. Using activity time windows and logical representation to reduce the complexity of biological network models: G1/S checkpoint pathway with DNA damage. Biosystems 2020; 191-192:104128. [DOI: 10.1016/j.biosystems.2020.104128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/25/2020] [Accepted: 02/25/2020] [Indexed: 01/14/2023]
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The Role of Hydrogen Peroxide and Peroxiredoxins throughout the Cell Cycle. Antioxidants (Basel) 2020; 9:antiox9040280. [PMID: 32224940 PMCID: PMC7222192 DOI: 10.3390/antiox9040280] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 01/22/2023] Open
Abstract
Hydrogen peroxide (H2O2) is an oxidizing agent that induces cellular damage at inappropriate concentrations and gives rise to an arrest during cell cycle progression, causing cell death. Recent evidence indicates that H2O2 also acts as a promoter for cell cycle progression by oxidizing specific thiol proteins. The intracellular concentration of H2O2 is regulated tightly, enabling its use as a cellular signaling molecule while minimizing its potential to cause cellular damage. Peroxiredoxins (Prxs) have peroxidase activity toward H2O2, organic hydroperoxides, and peroxynitrite for protecting cells from oxidative stress. They are suggested to work as signaling mediators, allowing the local accumulation of H2O2 by inactivating their peroxidase activity uniquely compared with other antioxidant proteins such as catalase and glutathione peroxidase. Given that Prxs are highly sensitive to oxidation by H2O2, they act as sensors and transducers of H2O2 signaling via transferring their oxidation state to effector proteins. The concentrations of intracellular H2O2 increase as the cell cycle progresses from G1 to mitosis. Here, we summarize the roles of Prxs with regard to the regulation of cell cycle-dependent kinase activity and anaphase-promoting complex/cyclosome in terms of changes in H2O2 levels. Protection of the cell from unwanted progression of the cell cycle is suggested to be a role of Prx. We discuss the possible roles of Prxs to control H2O2 levels.
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Al-Khafaji K, Taskin Tok T. Amygdalin as multi-target anticancer drug against targets of cell division cycle: double docking and molecular dynamics simulation. J Biomol Struct Dyn 2020; 39:1965-1974. [DOI: 10.1080/07391102.2020.1742792] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Khattab Al-Khafaji
- Faculty of Arts and Sciences, Department of Chemistry, Gaziantep University, Gaziantep, Turkey
| | - Tugba Taskin Tok
- Faculty of Arts and Sciences, Department of Chemistry, Gaziantep University, Gaziantep, Turkey
- Institute of Health Sciences, Department of Bioinformatics and Computational Biology, Gaziantep University, Gaziantep, Turkey
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Ma Y, Yan G, Han X, Zhang J, Xiong J, Miao W. Sexual cell cycle initiation is regulated by CDK19 and CYC9 in Tetrahymena thermophila. J Cell Sci 2020; 133:jcs235721. [PMID: 32041901 DOI: 10.1242/jcs.235721] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 01/27/2020] [Indexed: 01/31/2023] Open
Abstract
To investigate the mechanisms underlying initiation of the sexual cell cycle in eukaryotes, we have focused on cyclins and cyclin-dependent kinases (CDKs) in the well-studied model ciliate, Tetrahymena thermophila We identified two genes, CDK19 and CYC9, which are highly co-expressed with the mating-associated factors MTA, MTB and HAP2. Both CDK19 and CYC9 were found to be essential for mating in T. thermophila Subcellular localization experiments suggested that these proteins are located at the oral area, including the conjugation junction area, and that CDK19 or CYC9 knockout prevents mating. We found that CDK19 and CYC9 form a complex, and also identified several additional subunits, which may have regulatory or constitutive functions. RNA sequencing analyses and cytological experiments showed that mating is abnormal in both ΔCDK19 and ΔCYC9, mainly at the entry to the co-stimulation stage. These results indicate that the CDK19-CYC9 complex initiates the sexual cell cycle in T. thermophila.
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Affiliation(s)
- Yang Ma
- State Key Laboratory of Freshwater Ecology and Biotechnology, Wuhan 430072, China
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guanxiong Yan
- State Key Laboratory of Freshwater Ecology and Biotechnology, Wuhan 430072, China
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaojie Han
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- College of Fisheries and Life Science, Dalian Ocean University, Dalian 116023, China
| | - Jing Zhang
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Jie Xiong
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Wei Miao
- State Key Laboratory of Freshwater Ecology and Biotechnology, Wuhan 430072, China
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- CAS Center for Excellence in Animal Evolution and Genetics, Kunming 650223, China
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Al-Sanea MM. Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold. PeerJ 2020; 8:e8649. [PMID: 32206448 PMCID: PMC7075364 DOI: 10.7717/peerj.8649] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/27/2020] [Indexed: 01/30/2023] Open
Abstract
Background CDK8/CycC complex has kinase activity towards the carboxyterminal domain of RNA polymerase II, and contributes to the regulation of transcription via association with the mediator complex. Different human malignancies, mainly colorectal and gastric cancers, were produced as a result of overexpression of CDK8/CycC in the mediator complex. Therefore, CDK8/CycC complex represents as a cancer oncogene and it has become a potential target for developing CDK8/CycC modulators. Methods A series of nine 4-phenylaminoquinoline scaffold-based compounds 5a-i was synthesized, and biologically evaluated as potential CDK8/CycC complex inhibitors. Results The scaffold substituent effects on the intrinsic inhibitory activity toward CDK8/CycC complex are addressed trying to present a novel outlook of CDK8/CycC Complex inhibitors with 4-phenylaminoquinoline scaffold in cancer therapy. The secondary benzenesulfonamide analogues proved to be the most potent compounds in suppressing CDK8/CycC enzyme, whereas, their primary benzenesulfonamide analogues showed inferior activity. Moreover, the benzene reversed sulfonamide analogues were totally inactive. Discussion The titled scaffold showed promising inhibitory activity data and there is a crucial role of un/substituted sulfonamido group for CDK8/CycC complex inhibitory activity. Compound 5d showed submicromolar potency against CDK8/CycC (IC50 = 0.639 µM) and it can be used for further investigations and to design another larger library of phenylaminoquinoline scaffold-based analogues in order to establish detailed SARs.
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Affiliation(s)
- Mohammad M Al-Sanea
- Pharmaceutical Chemistry Department, College of Pharmacy, Jouf University, Sakaka, Aljouf, Saudi Arabia
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Pérez-Posada A, Dudin O, Ocaña-Pallarès E, Ruiz-Trillo I, Ondracka A. Cell cycle transcriptomics of Capsaspora provides insights into the evolution of cyclin-CDK machinery. PLoS Genet 2020; 16:e1008584. [PMID: 32176685 PMCID: PMC7098662 DOI: 10.1371/journal.pgen.1008584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 03/26/2020] [Accepted: 12/23/2019] [Indexed: 12/19/2022] Open
Abstract
Progression through the cell cycle in eukaryotes is regulated on multiple levels. The main driver of the cell cycle progression is the periodic activity of cyclin-dependent kinase (CDK) complexes. In parallel, transcription during the cell cycle is regulated by a transcriptional program that ensures the just-in-time gene expression. Many core cell cycle regulators are widely conserved in eukaryotes, among them cyclins and CDKs; however, periodic transcriptional programs are divergent between distantly related species. In addition, many otherwise conserved cell cycle regulators have been lost and independently evolved in yeast, a widely used model organism for cell cycle research. For a better understanding of the evolution of the cell cycle regulation in opisthokonts, we investigated the transcriptional program during the cell cycle of the filasterean Capsaspora owczarzaki, a unicellular species closely related to animals. We developed a protocol for cell cycle synchronization in Capsaspora cultures and assessed gene expression over time across the entire cell cycle. We identified a set of 801 periodic genes that grouped into five clusters of expression over time. Comparison with datasets from other eukaryotes revealed that the periodic transcriptional program of Capsaspora is most similar to that of animal cells. We found that orthologues of cyclin A, B and E are expressed at the same cell cycle stages as in human cells and in the same temporal order. However, in contrast to human cells where these cyclins interact with multiple CDKs, Capsaspora cyclins likely interact with a single ancestral CDK1-3. Thus, the Capsaspora cyclin-CDK system could represent an intermediate state in the evolution of animal-like cyclin-CDK regulation. Overall, our results demonstrate that Capsaspora could be a useful unicellular model system for animal cell cycle regulation.
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Affiliation(s)
- Alberto Pérez-Posada
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
| | - Omaya Dudin
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
| | - Eduard Ocaña-Pallarès
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
| | - Iñaki Ruiz-Trillo
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
- Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Barcelona, Catalonia, Spain
- ICREA, Barcelona, Catalonia, Spain
| | - Andrej Ondracka
- Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Barcelona, Catalonia, Spain
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Sadek K, Abouzed T, Nasr S, Shoukry M. Licochalcone B Ameliorates Liver Cancer via Targeting of Apoptotic Genes, DNA Repair Systems, and Cell Cycle Control. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2020; 19:372-386. [PMID: 33841550 PMCID: PMC8019863 DOI: 10.22037/ijpr.2020.1101292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a ubiquitous multifunctional protein required in the DNA base excision repair pathway and a noteworthy reducing-oxidizing factor that regulates the activity of various transcription factors. Cyclin-dependent kinases (CDKs) assume a key role in directing the progression of the cell- cycle. The present study evaluated the synergistic efficacy of using licochalcone B (LCB) and fullerene C60 (FnC60) nanoparticles against diethylnitrosamine (DEN)-induced hepatocarcinoma in rats and relevant signaling pathways, with APE1/Ref-1 and CDK-4, as novel anti-cancer- targeting. LCB alone and in combination with FnC60 significantly decreased DNA fragmentation, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine levels), APE1/Ref-1, CDK-4, retinoblastoma, B- cell lymphoma-2 (Bcl-2), B-cell lymphoma-xL (Bcl-xL), and β-arrestin-2 mRNA expression, and APE1/Ref-1 and CDK-4 protein expression. In contrast, these treatments significantly increased the expression of protein 53 (p53), Bcl-2-associated X protein (Bax), and caspase-3. These data suggest that LCB either alone or in combination with FnC60 elicited significant protective effects against DEN-induced hepatocarcinogenesis, which may have occurred because of the regulation of enzymes involved in DNA repair and cell-cycle control at S phase progression as well as the induction of apoptosis at the gene and protein expression levels. Furthermore, FnC60 potentiated the effect of LCB at the molecular level, possibly through targeting of cancerous cells.
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Affiliation(s)
- Kadry Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Egypt.
| | - Tarek Abouzed
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Egypt.
| | - Sherif Nasr
- Department of Molecular Biology and Genetic Engineering, Faculty of Veterinary Medicine, Damanhur University, Egypt.
| | - Moustafa Shoukry
- Department of Physiology, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Egypt.
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Xu Y, Tian Y, Zhao H, Zheng N, Ren K, Li Q. A novel CDK-2 homolog identified in lamprey, Lampetra japonica, with roles in apoptosis. FISH PHYSIOLOGY AND BIOCHEMISTRY 2019; 45:1829-1843. [PMID: 31325080 DOI: 10.1007/s10695-019-00683-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 07/02/2019] [Indexed: 06/10/2023]
Abstract
CDK-2, a member of the cyclin-dependent kinase family, plays an important role in many cell processes, such as cell cycle regulation, cell growth and differentiation, and cell apoptosis. Lampreys belong to the most primitive vertebrates, and there is no report about the CDK-2 gene in lampreys at present. In this study, a CDK-2-like gene sequence and deduced amino acid sequence were identified in Japanese lamprey (Lampetra japonica, L. japonica). The CDK-2-like gene has about 80% similarity with its homologs in jaw vertebrates. The polyclonal antibody against CDK-2-like was well prepared, and the results showed that CDK-2-like was highly expressed in the gonad tissue of lampreys. Apoptosis could reduce the expression of CDK-2-like in lymphocytes of lamprey, while overexpression of CDK-2-like could inhibit apoptosis. In addition, inhibition of CDK-2-like activity was able to trigger out apoptosis and also helped apoptotic inducer actinomycin D (Act-D) to induce apoptosis. These results suggest that CDK-2-like identified from lamprey may play a crucial role in apoptosis of jawless vertebrates.
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Affiliation(s)
- Yang Xu
- College of Life Science, Liaoning Normal University, Dalian, 116081, China.
- Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China.
| | - Yang Tian
- College of Life Science, Liaoning Normal University, Dalian, 116081, China
- Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China
| | - Huan Zhao
- College of Life Science, Liaoning Normal University, Dalian, 116081, China
- Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China
| | - Nan Zheng
- College of Life Science, Liaoning Normal University, Dalian, 116081, China
- Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China
| | - Kaixia Ren
- College of Life Science, Liaoning Normal University, Dalian, 116081, China
- Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China
| | - Qingwei Li
- College of Life Science, Liaoning Normal University, Dalian, 116081, China.
- Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China.
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Lan L, Wang H, Yang R, Liu F, Bi Q, Wang S, Wei X, Yan H, Su R. R2-8018 reduces the proliferation and migration of non-small cell lung cancer cells by disturbing transactivation between M3R and EGFR. Life Sci 2019; 234:116742. [PMID: 31401315 DOI: 10.1016/j.lfs.2019.116742] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 08/03/2019] [Accepted: 08/07/2019] [Indexed: 01/23/2023]
Abstract
AIMS The M3 muscarinic acetylcholine receptor (M3R) is a G protein-coupled receptor that is expressed in cases of non-small cell lung cancer (NSCLC). Previous studies demonstrated that M3R antagonists reduce the proliferation of NSCLC. However, how antagonists inhibit the NSCLC proliferation and migration is still little known. This study aims to investigate the mechanism of M3R involved in the growth of NSCLC. MAIN METHODS The CRISPR/Cas9 was used to knock out (KO) the M3R gene. A real-time cell analyzer (RTCA) was used to record the proliferation of NSCLC cells. The migration and cell cycle of NSCLC cells were evaluated with scratch test and flow cytometry (FCM), respectively. Antibody microarray analysis was performed to detect the expression of proteins after antagonizing M3R and knocking out of M3R, subsequently some of these important proteins were verified by western blot. KEY FINDINGS The proliferation and migration of NSCLC cells were inhibited by M3R antagonist R2-8018 and knocking out of M3R. Antagonism or knocking out of M3R reduced the phosphorylation of EGFR. Moreover, c-Src and β-arrestin-1 are involved in the mechanism of how the inhibition of M3R affects EGFR in NSCLC. Further study demonstrated that PI3K/AKT and MEK/ERK signal pathways are involved in M3R-induced EGFR transactivation in NSCLC, and the molecules involved in the cell cycle progression and migration of NSCLC cells were identified. SIGNIFICANCE This further understanding of the relationship between M3R and NSCLC facilitates the design of therapeutic strategy with M3R antagonist as an adjuvant drug for NSCLC treatment.
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Affiliation(s)
- Liting Lan
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China
| | - Hua Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China; 69242 Force Health Center, No. 1, Hongxing Road, Turpan, Xinjiang 838000, China
| | - Rui Yang
- National Institutes for Food and Drug Control, No. 31, Huatuo Road, Daxing District, Beijing 102629, China
| | - Fengqi Liu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China; Department of Medical Laboratory, Changzhi Medical College, No.161 Jiefang East Street, Changzhi, Shanxi, 046000, China
| | - Qingshang Bi
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China; Department of Medical Laboratory, Changzhi Medical College, No.161 Jiefang East Street, Changzhi, Shanxi, 046000, China
| | - Shiqi Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China; Center for Drug Evaluation, NMPA. No. 128, Jianguo Road, Chaoyang District, Beijing 100022, China
| | - Xiaoli Wei
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China
| | - Haitao Yan
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
| | - Ruibin Su
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
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Afzal A, Sarfraz M, Li GL, Ji SP, Duan SF, Khan NH, Wu DD, Ji XY. Taking a holistic view of PEST-containing nuclear protein (PCNP) in cancer biology. Cancer Med 2019; 8:6335-6343. [PMID: 31487123 PMCID: PMC6797571 DOI: 10.1002/cam4.2465] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/11/2019] [Accepted: 07/12/2019] [Indexed: 12/15/2022] Open
Abstract
Polypeptide sequences enriched with proline (P), glutamic acid (E), aspartic acid (D) and serine (S)/ threonine (T) (PEST) have been reported to be the most abundant and frequently distributed at the cellular level. There is growing evidence that PEST sequences act as proteolytic recognition signals for degradation of residual proteins which is critical for activation or deactivation of regulatory proteins involved in cellular signaling pathways of cell growth, differentiation, stress responses and physiological death. A PEST containing nuclear protein (PCNP) was demonstrated as a tumor suppressor in a neuroblastoma cancer model and tumor promoter in lung adenocarcinoma cancer model. Its unique properties like ubiquitination by NIRF, co‐localization with NIRF in nucleus and tumor progression attract the attention of researchers. PCNP was reported to be ubiquitinated by ring finger protein NIRF in E3 ligase manner and as modulator of MAPK and PI3K/AKT/mTOR signaling pathways. In this review, we summarize PCNP linked DNA damage response, Post translational modifications, and transportation to address initiation, prognosis, and resistance of tumor cells in terms of cell cycle regulation, transcription and apoptosis. Hence, we demonstrate PCNP as a novel target in cancer diagnosis and treatment.
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Affiliation(s)
- Attia Afzal
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China.,Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Muhammad Sarfraz
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China.,Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan.,Muncipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Henan University, Kaifeng, China
| | - Guang-Lei Li
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
| | - Shao-Ping Ji
- Muncipal Key Laboratory of Cell Signal Transduction, Henan Provincial Engineering Centre for Tumor Molecular Medicine, Henan University, Kaifeng, China
| | - Shao-Feng Duan
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China.,Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, China
| | - Nazeer Hussain Khan
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China.,School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, China.,Kaifeng Key Laboratory of Infection and Biological Safety (KLIBS), Henan University College of Medicine, Kaifeng, China
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42
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Henri P, Prevel C, Pellerano M, Lacotte J, Stoebner PE, Morris MC, Meunier L. Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity. Br J Dermatol 2019; 182:678-689. [PMID: 31145809 DOI: 10.1111/bjd.18178] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND The cyclin-dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK 4A (p16) bind CDK4/6 kinases and prevent their interaction with D-type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK-cyclin complexes and prevent their activation. OBJECTIVES To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis. METHODS A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real-time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors. RESULTS CDK2-cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4-cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis. CONCLUSIONS Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin-dependent kinases (CDKs) are involved in cell-cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T-cell-driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post-translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may constitute a promising therapeutic strategy.
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Affiliation(s)
- P Henri
- Institute of Biomolecules Max Mousseron (IBMM), University of Montpellier, UMR CNRS 5247, Montpellier, France
| | - C Prevel
- Institute of Biomolecules Max Mousseron (IBMM), University of Montpellier, UMR CNRS 5247, Montpellier, France
| | - M Pellerano
- Institute of Biomolecules Max Mousseron (IBMM), University of Montpellier, UMR CNRS 5247, Montpellier, France
| | - J Lacotte
- Department of Dermatology, Caremeau University Hospital, Nîmes, France
| | - P E Stoebner
- Institute of Biomolecules Max Mousseron (IBMM), University of Montpellier, UMR CNRS 5247, Montpellier, France.,Department of Dermatology, Caremeau University Hospital, Nîmes, France
| | - M C Morris
- Institute of Biomolecules Max Mousseron (IBMM), University of Montpellier, UMR CNRS 5247, Montpellier, France
| | - L Meunier
- Institute of Biomolecules Max Mousseron (IBMM), University of Montpellier, UMR CNRS 5247, Montpellier, France.,Department of Dermatology, Caremeau University Hospital, Nîmes, France
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MiR-200-3p Is Potentially Involved in Cell Cycle Arrest by Regulating Cyclin A during Aestivation in Apostichopus japonicus. Cells 2019; 8:cells8080843. [PMID: 31390757 PMCID: PMC6721757 DOI: 10.3390/cells8080843] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/02/2019] [Accepted: 08/04/2019] [Indexed: 11/16/2022] Open
Abstract
The sea cucumber (Apostichopus japonicus) has become a good model organism for studying environmentally induced aestivation in marine invertebrates. We hypothesized that mechanisms that arrest energy-expensive cell cycle activity would contribute significantly to establishing the hypometabolic state during aestivation. Cyclin A is a core and particularly interesting cell cycle regulator that functions in both the S phase and in mitosis. In the present study, negative relationships between miR-200-3p and AjCA expressions were detected at both the transcriptional and the translational levels during aestivation in A. japonicus. Dual-luciferase reporter assays confirmed the targeted location of the miR-200-3p binding site within the AjCA gene transcript. Furthermore, gain- and loss-of-function experiments were conducted in vivo with sea cucumbers to verify the interaction between miR-200-3p and AjCA in intestine tissue by qRT-PCR and Western blotting. The results show that the overexpression of miR-200-3p mimics suppressed AjCA transcript levels and translated protein production, whereas transfection with a miR-200-3p inhibitor enhanced both AjCA mRNA and AjCA protein in A. japonicus intestine. Our findings suggested a potential mechanism that reversibly arrests cell cycle progression during aestivation, which may center on miR-200-3p inhibitory control over the translation of cyclin A mRNA transcripts.
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Temporal Proteomic Analysis of BK Polyomavirus Infection Reveals Virus-Induced G 2 Arrest and Highly Effective Evasion of Innate Immune Sensing. J Virol 2019; 93:JVI.00595-19. [PMID: 31142673 PMCID: PMC6675895 DOI: 10.1128/jvi.00595-19] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 05/18/2019] [Indexed: 12/13/2022] Open
Abstract
BK polyomavirus (BKPyV) is a small DNA virus that establishes a life-long persistent infection in the urinary tract of most people. BKPyV is known to cause severe morbidity in renal transplant recipients and can lead to graft rejection. The simple 5.2-kbp double-stranded DNA (dsDNA) genome expresses just seven known proteins; thus, it relies heavily on the host machinery to replicate. How the host proteome changes over the course of infection is key to understanding this host-virus interplay. Here, for the first time quantitative temporal viromics has been used to quantify global changes in >9,000 host proteins in two types of primary human epithelial cells throughout 72 h of BKPyV infection. These data demonstrate the importance of cell cycle progression and pseudo-G2 arrest in effective BKPyV replication, along with a surprising lack of an innate immune response throughout the whole virus replication cycle. BKPyV thus evades pathogen recognition to prevent activation of innate immune responses in a sophisticated manner.IMPORTANCE BK polyomavirus can cause serious problems in immune-suppressed patients, in particular, kidney transplant recipients who can develop polyomavirus-associated kidney disease. In this work, we have used advanced proteomics techniques to determine the changes to protein expression caused by infection of two independent primary cell types of the human urinary tract (kidney and bladder) throughout the replication cycle of this virus. Our findings have uncovered new details of a specific form of cell cycle arrest caused by this virus, and, importantly, we have identified that this virus has a remarkable ability to evade detection by host cell defense systems. In addition, our data provide an important resource for the future study of kidney epithelial cells and their infection by urinary tract pathogens.
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C/EBPβ Is a Transcriptional Regulator of Wee1 at the G₂/M Phase of the Cell Cycle. Cells 2019; 8:cells8020145. [PMID: 30754676 PMCID: PMC6407104 DOI: 10.3390/cells8020145] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/06/2019] [Accepted: 02/09/2019] [Indexed: 12/25/2022] Open
Abstract
The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein were expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying the G2/M transition in the cell cycle. In C/EBPβ-knockdown cells, a prolonged increase in phosphorylation of cyclin dependent kinase 1 at tyrosine 15 (Y15-pCDK1) was displayed with simultaneously increased Wee1 and decreased Cdc25B expression. Chromatin immunoprecipitation (ChIP) analysis showed that C/EBPβ bound to distal promoter regions of WEE1 and repressed WEE1 transcription through its interaction with histone deacetylase 2. Treatment of C/EBPβ-knockdown cells with a Wee1 inhibitor induced a decrease in Y15-pCDK1 and recovered cells from G2/M arrest. In the xenograft tumors, the depletion of C/EBPβ significantly reduced tumor growth. Taken together, these results indicate that Wee1 is a novel transcription target of C/EBPβ that is required for the G2/M phase of cell cycle progression, ultimately regulating proliferation of NSCLC cells.
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Orság P, Havran L, Fojt L, Coufal J, Brázda V, Fojta M. Voltammetric behavior of a candidate anticancer drug roscovitine at carbon electrodes in aqueous buffers and a cell culture medium. MONATSHEFTE FUR CHEMIE 2019. [DOI: 10.1007/s00706-018-2333-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Krishna L, Dhamodaran K, Subramani M, Ponnulagu M, Jeyabalan N, Krishna Meka SR, Jayadev C, Shetty R, Chatterjee K, Khora SS, Das D. Protective Role of Decellularized Human Amniotic Membrane from Oxidative Stress-Induced Damage on Retinal Pigment Epithelial Cells. ACS Biomater Sci Eng 2018; 5:357-372. [DOI: 10.1021/acsbiomaterials.8b00769] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Lekshmi Krishna
- Stem Cell Research Lab, GROW Laboratories, Narayana Nethralaya Foundation, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
- School of Bioscience and Technology, VIT University, Vellore, Tamil Nadu, India
| | - Kamesh Dhamodaran
- Stem Cell Research Lab, GROW Laboratories, Narayana Nethralaya Foundation, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
| | - Murali Subramani
- Stem Cell Research Lab, GROW Laboratories, Narayana Nethralaya Foundation, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
| | - Murugeswari Ponnulagu
- Stem Cell Research Lab, GROW Laboratories, Narayana Nethralaya Foundation, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
| | - Nallathambi Jeyabalan
- Grow Laboratories, Narayana Nethralaya Foundation, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
| | - Sai Rama Krishna Meka
- Department of Materials Engineering, Indian Institute of Science, Bangalore, Karnataka, India
| | - Chaitra Jayadev
- Department of Vitreo-retinal Services, Narayana Nethralaya Eye Institute, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
| | - Rohit Shetty
- Department of Cornea and Refractive Surgery, Narayana Nethralaya Eye Institute, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
| | - Kaushik Chatterjee
- Department of Materials Engineering, Indian Institute of Science, Bangalore, Karnataka, India
| | | | - Debashish Das
- Stem Cell Research Lab, GROW Laboratories, Narayana Nethralaya Foundation, 258/A, Bommasandra Industrial Area, Bangalore, Karnataka, India
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Feng S, Zhu J, Xia K, Yu W, Wang Y, Wang J, Li F, Yang Z, Yang X, Liu B, Tao H, Liang C. Cantharidin Inhibits Anti-Apoptotic Bcl-2 Family Proteins and Induces Apoptosis in Human Osteosarcoma Cell Lines MG-63 and MNNG/HOS via Mitochondria-Dependent Pathway. Med Sci Monit 2018; 24:6742-6749. [PMID: 30248086 PMCID: PMC6180936 DOI: 10.12659/msm.910294] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Cantharidin (CTD) is one of the major active ingredients of blister beetles and has significant antitumor activity in many cancer cell lines. The aim of our study was to evaluate the effect of CTD on the apoptosis of human osteosarcoma cells MG-63 and MNNG/HOS, and to explore the possible molecular mechanism. Material/Methods Osteosarcoma cells MG-63 and MNNG/HOS were treated with varying concentrations of CTD. The proliferation inhibition of cells was detected by MTS. Flow cytometry and Hoechst 33258 staining were used to determine cell cycle arrest and apoptosis, and apoptosis-related protein levels were analyzed by Western blotting. Results Our current findings suggest that CTD could inhibit the proliferation of these 2 osteosarcoma cells. The cells treated with CTD showed an obvious apoptotic morphology, and CTD promoted cells apoptosis in a dose-dependent manner. In addition, cantharidin-induced apoptosis was accompanied by increased expression of Bax and PARP and decreased expression of Bcl-2, p-Akt, and p-Cdc2. Conclusions CTD accelerates the apoptosis of MG-63 and MNNG/HOS cells in a concentration-dependent manner through the mitochondria-dependent pathway, suggesting that use of CTD is a novel approach for the treatment of osteosarcoma.
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Affiliation(s)
- Shoumin Feng
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Jian Zhu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Kaishun Xia
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Wei Yu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Yitian Wang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Junjie Wang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Fangcai Li
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Zhengming Yang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Xiaobo Yang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Bing Liu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Huimin Tao
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Chengzhen Liang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China (mainland)
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Pandey N, Vinod PK. Mathematical modelling of reversible transition between quiescence and proliferation. PLoS One 2018; 13:e0198420. [PMID: 29856829 PMCID: PMC5983510 DOI: 10.1371/journal.pone.0198420] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 05/19/2018] [Indexed: 11/18/2022] Open
Abstract
Cells switch between quiescence and proliferation states for maintaining tissue homeostasis and regeneration. At the restriction point (R-point), cells become irreversibly committed to the completion of the cell cycle independent of mitogen. The mechanism involving hyper-phosphorylation of retinoblastoma (Rb) and activation of transcription factor E2F is linked to the R-point passage. However, stress stimuli trigger exit from the cell cycle back to the mitogen-sensitive quiescent state after Rb hyper-phosphorylation but only until APC/CCdh1 inactivation. In this study, we developed a mathematical model to investigate the reversible transition between quiescence and proliferation in mammalian cells with respect to mitogen and stress signals. The model integrates the current mechanistic knowledge and accounts for the recent experimental observations with cells exiting quiescence and proliferating cells. We show that Cyclin E:Cdk2 couples Rb-E2F and APC/CCdh1 bistable switches and temporally segregates the R-point and the G1/S transition. A redox-dependent mutual antagonism between APC/CCdh1 and its inhibitor Emi1 makes the inactivation of APC/CCdh1 bistable. We show that the levels of Cdk inhibitor (CKI) and mitogen control the reversible transition between quiescence and proliferation. Further, we propose that shifting of the mitogen-induced transcriptional program to G2-phase in proliferating cells might result in an intermediate Cdk2 activity at the mitotic exit and in the immediate inactivation of APC/CCdh1. Our study builds a coherent framework and generates hypotheses that can be further explored by experiments.
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Affiliation(s)
- Nishtha Pandey
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, India
| | - P. K. Vinod
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, India
- * E-mail:
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50
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Wang Y, Wang R, Li Y, Sun Y, Song C, Zhan Y, Tan L, Liao Y, Meng C, Qiu X, Ding C. Newcastle disease virus induces G 0/G 1 cell cycle arrest in asynchronously growing cells. Virology 2018; 520:67-74. [PMID: 29793075 PMCID: PMC7112094 DOI: 10.1016/j.virol.2018.05.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 05/03/2018] [Accepted: 05/08/2018] [Indexed: 12/02/2022]
Abstract
The cell cycle, as a basic cellular process, is conservatively regulated. Consequently, subversion of the host cell replication cycle is a common strategy employed by many viruses to create a cellular environment favorable for viral replication. Newcastle disease virus (NDV) causes disease in poultry and is also an effective oncolytic agent. However, the effects of NDV infection on cell cycle progression are unknown. In this study, we showed that NDV replication in asynchronized cells resulted in the accumulation of infected cells in the G0/G1 phase of the cell cycle, which benefitted the proliferation of NDV. Examination of various cell cycle-regulatory proteins showed that expression of cyclin D1, was significantly reduced following NDV infection. Importantly, the decreased expression of cyclin D1 was reversed by inhibition of CHOP expression, indicating that induction of the PERK-eIF-2a-ATF4-CHOP signaling pathway was involved in the G0/G1 phase cell cycle arrest observed following NDV infection.
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Affiliation(s)
- Yan Wang
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Rui Wang
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China; Yangzhou University, Yangzhou 225000, PR China
| | - Yanrong Li
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Yingjie Sun
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Cuiping Song
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Yuan Zhan
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Lei Tan
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Ying Liao
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - ChunChun Meng
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Xusheng Qiu
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China
| | - Chan Ding
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, PR China.
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