Genetic interrogation of replicative senescence uncovers a dual role for USP28 in coordinating the p53 and GATA4 branches of the senescence program

Genes Dev. 2017 Oct 1;31(19):1933-1938. doi: 10.1101/gad.304857.117.

Abstract

Senescence is a terminal differentiation program that halts the growth of damaged cells and must be circumvented for cancer to arise. Here we describe a panel of genetic screens to identify genes required for replicative senescence. We uncover a role in senescence for the potent tumor suppressor and ATM substrate USP28. USP28 controls activation of both the TP53 branch and the GATA4/NFkB branch that controls the senescence-associated secretory phenotype (SASP). These results suggest a role for ubiquitination in senescence and imply a common node downstream from ATM that links the TP53 and GATA4 branches of the senescence response.

Keywords: GATA4; USP28; senescence.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Cellular Senescence / genetics*
  • GATA4 Transcription Factor / genetics
  • GATA4 Transcription Factor / metabolism*
  • Gene Expression Regulation*
  • Gene Library
  • HCT116 Cells
  • Humans
  • Reproducibility of Results
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination

Substances

  • GATA4 Transcription Factor
  • GATA4 protein, human
  • Tumor Suppressor Protein p53
  • USP28 protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Ubiquitin Thiolesterase