Studying the role of MSP58 in regulation of telomerase/hTERT and cellular senescence

Abstract

58-kDa microspherule protein (MSP58) plays an important role in a variety of cellular function including transcriptional regulation cell proliferation and oncogenic transformation To date the mechanisms underlying the oncogenic effect of MSP58 remain elusive In our study MSP58 silencing by siRNA results in aneuploidy and apoptosis Forced expression of MSP58 induces either cellular senescence or transformation dependent on the integrity of a senescence program controlled by functional p53 MSP58 overexpression induces premature senescence in HT1080 NIH3T3 cell lines human mammary epithelial cell line (H184B5F5/M10) and normal human diploid fibroblasts (Hs68 and IMR90) through hypophosporylated Rb activation of the DNA damage response and upregulation of p53/p21 pathway Importantly p53 is required for MSP58-induced premature senescence Furthermore novel MSP58-interacting proteins were identified by yeast two-hybrid screen including the Brg1 (Brahma-related gene 1) and TEIF (telomerase transcriptional elements-interacting factor) Notably MSP58 complex colocalizes with both p53 and Brg1 on the p21 promoter and collaborate to activate p21 gene transcription Brg1 or p53 knockdown by RNA interferences results in MSP58-mediated senescence bypassed Additionally MSP58 serves as a negative regulator of hTERT transcription and suppresses TEIF-induced hTERT transcriptional activity telomerase activity cell proliferation and tumor formation The inhibitory effect of MSP58 on hTERT transcription occurred through inhibition of TEIF binding to DNA Analysis the expression level of MSP58 in tumor and normal samples in tissue microarrays showed that MSP58 was both up-regulated and down-regulated in different types of tumors compared to the normal tissue counterparts Taken together these studies provide new insights into the role of MSP58 in regulation of cellular proliferation and telomerase activity via different interacting proteins and suggest that MSP58 has both oncogenic and tumor-suppressive properties

Date of Award	2014 Jan 23
Original language	English
Supervisor	Ding-Yen Lin (Supervisor)