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)

Che Chia Hsu, Chang Han Chen, Tsung I. Hsu, Jan Jong Hung, Jiunn Liang Ko, Bo Zhang, Yi Chao Lee, Han Ku Chen, Wen Chang Chang, Ding Yen Lin

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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 of hTERT promoter. 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.

Original languageEnglish
Pages (from-to)565-579
Number of pages15
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1843
Issue number3
DOIs
Publication statusPublished - Mar 2014
Externally publishedYes

Keywords

  • 58-kDa microspherule protein
  • Human telomerase reverse transcriptase
  • Telomerase
  • Telomerase transcriptional element-interacting factor

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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