p73 supports cellular growth through c-Jun-dependent AP-1 transactivation

Nat Cell Biol. 2007 Jun;9(6):698-705. doi: 10.1038/ncb1598. Epub 2007 May 13.

Abstract

The cause or consequence of overexpression of p73 (refs 1, 2), the structural and functional homologue of the tumour-suppressor gene product p53 (refs 3, 4), in human cancers is poorly understood. Here, we report a role for p73 in supporting cellular growth through the upregulation of AP-1 transcriptional activity. p73 suppresses growth when overexpressed alone, but synergises with the proto-oncogene c-Jun to promote cellular survival. Conversely, silencing of p73 expression compromises cellular proliferation. Molecular analysis revealed that expression of the AP-1 target-gene product cyclinD1 (ref. 5) is reduced concomitant with p73, but not p53, silencing. Moreover, cyclinD1 was induced by p73 expression in a c-Jun-dependent manner, and was required for p73-mediated cell survival. Furthermore, c-Jun-dependent AP-1 transcriptional activity was augmented by p73 and, consistently, induction of endogenous AP-1 target genes was compromised in the absence of p73. Chromatin immunoprecipitation and electrophoretic mobility shift analysis indicated that p73 enhanced the binding of phosphorylated c-Jun and Fra-1, another AP-1 family member, to AP-1 consensus DNA sequences, by regulating c-Jun phosphorylation and Fra-1 expression. Collectively, our data demonstrates a novel and unexpected role of p73 in augmenting AP-1 transcriptional activity through which it supports cellular growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cell Survival / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cyclin D1 / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Binding / genetics
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation / genetics*
  • Tumor Protein p73
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation / genetics

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • TP73 protein, human
  • Transcription Factor AP-1
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • fos-related antigen 1
  • Cyclin D1