DN-p73 is activated after DNA damage in a p53-dependent manner to regulate p53-induced cell cycle arrest

Oncogene. 2002 May 23;21(23):3796-803. doi: 10.1038/sj.onc.1205465.

Abstract

p53 and p73 genes are both activated in response to DNA damage to induce either cell cycle arrest or apoptosis, depending on the strength and the quality of the damaging stimulus. p53/p73 transcriptional activity must be tightly regulated to ensure that the appropriate biological response is achieved and to allow the cell to re-enter into the cell cycle after the damage has been repaired. In addition to multiple transcriptionally active (TA) isoforms, dominant negative (DN) variants, that lack the amino-terminal transactivation domain and function as trans-repressors of p53, p63 and p73, are expressed from a second internal promoter (P2-p73Pr). Here we show that, in response to a non apoptotic DNA damage induced by low doses of doxorubicin, p53 binds in vivo, as detected by a p53-specific chromatin immunoprecipitation assay, and activates the P2-p73 promoter. DN-p73alpha protein accumulates under the same conditions and exogenously expressed DN-p73alpha is able to counteract the p53-induced activation of the P2-p73Pr. These results suggest that DN-p73 may contribute to the autoregulatory loops responsible for the termination of p53/p73 responses in cells that do not undergo apoptosis. Accordingly, the activation of the P2-p73Pr is markedly enhanced in both p73-/- murine fibroblasts and in human cells in which p73 transcripts are selectively knocked-out by p73-specific small interfering RNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Cycle* / drug effects
  • Cell Line
  • DNA Damage*
  • DNA-Binding Proteins / genetics*
  • Doxorubicin / pharmacology
  • Fibroblasts
  • Genes, Tumor Suppressor
  • Humans
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcriptional Activation*
  • Tumor Cells, Cultured
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • p73 protein, human
  • Doxorubicin