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58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway
The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regu...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391125/ https://www.ncbi.nlm.nih.gov/pubmed/22563078 http://dx.doi.org/10.1074/jbc.M111.335331 |
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author | Hsu, Che-Chia Lee, Yi-Chao Yeh, Shiu-Hwa Chen, Chang-Han Wu, Chih-Ching Wang, Tsui-Ying Chen, Yu-Nong Hung, Liang-Yi Liu, Yao-Wen Chen, Han-Ku Hsiao, Yi-Ting Wang, Wei-Sheng Tsou, Jen-Hui Tsou, Yi-Huan Wu, Mei-Hsiang Chang, Wen-Chang Lin, Ding-Yen |
author_facet | Hsu, Che-Chia Lee, Yi-Chao Yeh, Shiu-Hwa Chen, Chang-Han Wu, Chih-Ching Wang, Tsui-Ying Chen, Yu-Nong Hung, Liang-Yi Liu, Yao-Wen Chen, Han-Ku Hsiao, Yi-Ting Wang, Wei-Sheng Tsou, Jen-Hui Tsou, Yi-Huan Wu, Mei-Hsiang Chang, Wen-Chang Lin, Ding-Yen |
author_sort | Hsu, Che-Chia |
collection | PubMed |
description | The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated β-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties. |
format | Online Article Text |
id | pubmed-3391125 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-33911252012-07-11 58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway Hsu, Che-Chia Lee, Yi-Chao Yeh, Shiu-Hwa Chen, Chang-Han Wu, Chih-Ching Wang, Tsui-Ying Chen, Yu-Nong Hung, Liang-Yi Liu, Yao-Wen Chen, Han-Ku Hsiao, Yi-Ting Wang, Wei-Sheng Tsou, Jen-Hui Tsou, Yi-Huan Wu, Mei-Hsiang Chang, Wen-Chang Lin, Ding-Yen J Biol Chem Cell Biology The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated β-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties. American Society for Biochemistry and Molecular Biology 2012-06-29 2012-05-04 /pmc/articles/PMC3391125/ /pubmed/22563078 http://dx.doi.org/10.1074/jbc.M111.335331 Text en © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Cell Biology Hsu, Che-Chia Lee, Yi-Chao Yeh, Shiu-Hwa Chen, Chang-Han Wu, Chih-Ching Wang, Tsui-Ying Chen, Yu-Nong Hung, Liang-Yi Liu, Yao-Wen Chen, Han-Ku Hsiao, Yi-Ting Wang, Wei-Sheng Tsou, Jen-Hui Tsou, Yi-Huan Wu, Mei-Hsiang Chang, Wen-Chang Lin, Ding-Yen 58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway |
title | 58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway |
title_full | 58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway |
title_fullStr | 58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway |
title_full_unstemmed | 58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway |
title_short | 58-kDa Microspherule Protein (MSP58) Is Novel Brahma-related Gene 1 (BRG1)-associated Protein That Modulates p53/p21 Senescence Pathway |
title_sort | 58-kda microspherule protein (msp58) is novel brahma-related gene 1 (brg1)-associated protein that modulates p53/p21 senescence pathway |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391125/ https://www.ncbi.nlm.nih.gov/pubmed/22563078 http://dx.doi.org/10.1074/jbc.M111.335331 |
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