title: 58-kDa microspherule protein (MSP58) is novel Brahma-related gene 1 (BRG1)-associated protein that modulates p53/p21 senescence pathway.
abstract: 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.
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Che-Chia
authors.initials: CC
authors.lastname: Hsu
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.forename: Shiu-Hwa
authors.initials: SH
authors.lastname: Yeh
authors.forename: Chang-Han
authors.initials: CH
authors.lastname: Chen
authors.forename: Chih-Ching
authors.initials: CC
authors.lastname: Wu
authors.forename: Tsui-Ying
authors.initials: TY
authors.lastname: Wang
authors.forename: Yu-Nong
authors.initials: YN
authors.lastname: Chen
authors.forename: Liang-Yi
authors.initials: LY
authors.lastname: Hung
authors.forename: Yao-Wen
authors.initials: YW
authors.lastname: Liu
authors.forename: Han-Ku
authors.initials: HK
authors.lastname: Chen
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Hsiao
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Wang
authors.forename: Jen-Hui
authors.initials: JH
authors.lastname: Tsou
authors.forename: Yi-Huan
authors.initials: YH
authors.lastname: Tsou
authors.forename: Mei-Hsiang
authors.initials: MH
authors.lastname: Wu
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Ding-Yen
authors.initials: DY
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005354:Fibrosarcoma; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C113292:MCRS1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D015689:Oncogene Protein p21(ras)