HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53

Mi Huang, Duanzhuo Li, Yuwen Huang, Xiukun Cui, Shengjie Liao, Jiuxiang Wang, Fei Liu, Chang Li, Meng Gao, Jiaxiang Chen, Zhaohui Tang, David Wan Cheng Li, Mugen Liu

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The differentiation from constantly dividing epithelial cells into secondary fiber cells is a key step during lens development. Failure in this process, which requires cell proliferation inhibition and cell cycle exit, causes cataract formation. HSF4 (Heat Shock Transcription Factor 4) gene mutations may lead to both congenital and senile cataract. However, how HSF4 mutations induce cataract formation remains obscure. In this study, we demonstrate that HSF4 can suppress the proliferation of human lens epithelial cells (HLECs) by promoting G1/S arrest in a p53-dependent manner. In contrast, HSF4 with cataract causative mutations fail to cause cell cycle arrest and have no obvious effect on cell proliferation. We further identify that HSF4 recruits p53 in the nucleus and promotes its transcriptional activity, leading to the expression of its target gene p21 in HLECs. HSF4, but not its cataract-causing mutants, stabilizes p53 protein and inhibits its ubiquitin degradation. Our data reveal that HSF4 may work as a switch between lens epithelial cell proliferation and secondary fiber cell differentiation, a process which mainly depends on p53. Through demonstration of this novel downstream pathway of HSF4, our results help uncover the pathogenic mechanisms caused by HSF4 mutations.

Original languageEnglish (US)
Pages (from-to)1808-1817
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1853
Issue number8
DOIs
StatePublished - Aug 1 2015

Keywords

  • Cataract
  • Cell cycle arrest
  • GAPDH
  • GFP
  • GST
  • HSF4
  • P53 stability
  • Proliferation
  • QPCR
  • RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Huang, M., Li, D., Huang, Y., Cui, X., Liao, S., Wang, J., Liu, F., Li, C., Gao, M., Chen, J., Tang, Z., Li, D. W. C., & Liu, M. (2015). HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53. Biochimica et Biophysica Acta - Molecular Cell Research, 1853(8), 1808-1817. https://doi.org/10.1016/j.bbamcr.2015.04.018