title: The 58-kda microspherule protein (MSP58) represses human telomerase reverse transcriptase (hTERT) gene expression and cell proliferation by interacting with telomerase transcriptional element-interacting factor (TEIF).
abstract: 58-kDa microspherule protein (MSP58) plays an important role in a variety of cellular processes including transcriptional regulation, cell proliferation and oncogenic transformation. Currently, the mechanisms underlying the oncogenic effect of MSP58 are not fully understood. The human telomerase reverse transcriptase (hTERT) gene, which encodes an essential component for telomerase activity that is involved in cellular immortalization and transformation, is strictly regulated at the gene transcription level. Our previous study revealed a novel function of MSP58 in cellular senescence. Here we identify telomerase transcriptional element-interacting factor (TEIF) as a novel MSP58-interacting protein and determine the effect of MSP58 on hTERT transcription. This study thus provides evidence showing MSP58 to be a negative regulator of hTERT expression and telomerase activity. Luciferase reporter assays indicated that MSP58 could suppress the transcription ofhTERTpromoter. Additionally, stable overexpression of MSP58 protein in HT1080 and 293T cells decreased both endogenous hTERT expression and telomerase activity. Conversely, their upregulation was induced by MSP58 silencing. Chromatin immunoprecipitation assays showed that MSP58 binds to the hTERT proximal promoter. Furthermore, overexpression of MSP58 inhibited TEIF-mediated hTERT transactivation, telomerase activation, and cell proliferation promotion. The inhibitory effect of MSP58 occurred through inhibition of TEIF binding to DNA. Ultimately, the HT1080-implanted xenograft mouse model confirmed these cellular effects. Together, our findings provide new insights into both the biological function of MSP58 and the regulation of telomerase/hTERT expression.
authors.forename: Che-Chia
authors.initials: CC
authors.lastname: Hsu
authors.forename: Chang-Han
authors.initials: CH
authors.lastname: Chen
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Hsu
authors.forename: Jan-Jong
authors.initials: JJ
authors.lastname: Hung
authors.forename: Jiunn-Liang
authors.initials: JL
authors.lastname: Ko
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.forename: Han-Ku
authors.initials: HK
authors.lastname: Chen
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Ding-Yen
authors.initials: DY
authors.lastname: Lin
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; C113292:MCRS1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C464929:SCYL1 protein, human; D014157:Transcription Factors; C509186:TERT protein, human; D019098:Telomerase