TFIIS.h, a new target of p53, regulates transcription efficiency of pro-apoptotic bax gene

Sci Rep. 2016 Mar 23;6:23542. doi: 10.1038/srep23542.

Abstract

Tumor suppressor p53 transcriptionally regulates hundreds of genes involved in various cellular functions. However, the detailed mechanisms underlying the selection of p53 targets in response to different stresses are still elusive. Here, we identify TFIIS.h, a transcription elongation factor, as a new transcriptional target of p53, and also show that it can enhance the efficiency of transcription elongation of apoptosis-associated bax gene, but not cell cycle-associated p21 (CDKN1A) gene. TFIIS.h is revealed as a p53 target through microarray analysis of RNAs extracted from cells treated with or without inauhzin (INZ), a p53 activator, and further confirmed by RT-q-PCR, western blot, luciferase reporter, and ChIP assays. Interestingly, knocking down TFIIS.h impairs, but overexpressing TFIIS.h promotes, induction of bax, but not other p53 targets including p21, by p53 activation. In addition, overexpression of TFIIS.h induces cell death in a bax- dependent fashion. These findings reveal a mechanism by which p53 utilizes TFIIS.h to selectively promote the transcriptional elongation of the bax gene, upsurging cell death in response to severe DNA damage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Survival
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HCT116 Cells
  • Humans
  • Indoles / pharmacology
  • Oligonucleotide Array Sequence Analysis / methods
  • Phenothiazines / pharmacology
  • Promoter Regions, Genetic
  • Stomach Neoplasms / genetics*
  • Transcription, Genetic
  • Transcriptional Elongation Factors / genetics*
  • Transcriptional Elongation Factors / metabolism*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*
  • bcl-2-Associated X Protein / genetics*

Substances

  • 10-(2-(5H-(1,2,4)triazino(5,6-b)indol-3-ylthio)butanoyl)-10H-phenothiazine
  • BAX protein, human
  • Indoles
  • Phenothiazines
  • TP53 protein, human
  • Transcriptional Elongation Factors
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • transcription factor S-II