Modulation of p53 and p73 levels by cyclin G: Implication of a negative feedback regulation

Takao Ohtsuka, Hoon Ryu, Yohji A. Minamishima, Akihide Ryo, Sam W. Lee

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65 Citations (Scopus)

Abstract

Cyclin G is a transcriptional target gene of tumor suppressor p53. Recent studies present evidence that cyclin G may play a central role in the p53-Mdm2 autoregulated module, but the precise function of cyclin G remains elusive. Here, we show a negative effect of cyclin G on the stability of p53 and p73. Cyclin G expression resulted in a dramatic decrease of p53 protein levels in response to DNA damage and abrogated irradiation-mediated G1 arrest along with an increase of S phase in MCF7 cells containing wild-type p53. In p53-null Saos2 cells, cyclin G inhibited p73 induction in response to genotoxic stress and delayed the camptothecin-mediated cell cycle arrest. Cyclin G interacts with p53 as well as p73, and its binding to p53 or p73 presumably mediates downregulation of p53 and p73. We also found that cyclin G-mediated reduction of p53 but not of p73 is Mdm2-dependent. Moreover, inhibition of cyclin G by small interfering RNA (siRNA) caused the accumulation of p53 and p73 protein levels in response to DNA damage. Therefore, our results imply that cyclin G is transcriptionally activated by p53 or p73, and, in turn, cyclin G negatively regulates the stabilization of p53 family proteins through an unknown mechanism different from ubiquitination or transcriptional control.

Original languageEnglish
Pages (from-to)1678-1687
Number of pages10
JournalOncogene
Volume22
Issue number11
DOIs
Publication statusPublished - 2003 Mar 20

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Keywords

  • Cyclin G
  • Negative feedback regulation
  • p53
  • p73
  • siRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Ohtsuka, T., Ryu, H., Minamishima, Y. A., Ryo, A., & Lee, S. W. (2003). Modulation of p53 and p73 levels by cyclin G: Implication of a negative feedback regulation. Oncogene, 22(11), 1678-1687. https://doi.org/10.1038/sj.onc.1206306