The nucleolar protein 58-kDa microspherule protein (MSP58) is a candidate oncogene implicated in modulating cellular proliferation. In our studies, acute depletion of MSP58 expression using short hairpin (sh)RNA synthesis led to aneuploidy and apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Remarkably, ectopic expression of MSP58 in HT1080, NIH3T3, normal human fibroblasts, and mammary epithelial cell lines resulted in induction of premature senescence, caused large and flattened cell morphology, and increased senescence-associated β-galactosidase activity. This phenotype was accompanied by hypophosphorylated Rb, elevation of p53 and p21 protein expressions, activation of p53-mediated transcription, accumulation of phosphorylated forms of ATM/ATR and Chk1/Chk2 kinases, and formation of γH2AX and RPA70 foci, indicating that MSP58 activates the DNA damage response (DDR) and p53/p21 signaling pathways. Furthermore, we identified the SWI/SNF chromatin remodeling subunit, BRG1, as a critical mediator of MSP58-induced senescence. MSP58, BRG1, and p53 form a ternary complex on the p21 promoter, and collaborate to activate p21. This study revealed novel links among MSP58, p53, and cellular senescence in human tumors and normal cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3955. doi:1538-7445.AM2012-3955

©2012 American Association for Cancer Research
2012