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

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.
Authors	Takao Ohtsuka, Hoon Ryu, Yohji A Minamishima, Akihide Ryo, Sam W Lee
Journal	Oncogene (Oncogene) Vol. 22 Issue 11 Pg. 1678-87 (Mar 20 2003) ISSN: 0950-9232 [Print] England
PMID	12642871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	CCNG1 protein, human Cyclin G Cyclin G1 Cyclins DNA-Binding Proteins Nuclear Proteins Proto-Oncogene Proteins TP73 protein, human Tumor Protein p73 Tumor Suppressor Protein p53 Tumor Suppressor Proteins Ubiquitin MDM2 protein, human Proto-Oncogene Proteins c-mdm2
Topics	Blotting, Northern Blotting, Western Cell Cycle Cell Separation Cyclin G Cyclin G1 Cyclins (metabolism, physiology) DNA-Binding Proteins (metabolism) Down-Regulation Flow Cytometry Genes, Tumor Suppressor Humans Nuclear Proteins (metabolism) Proto-Oncogene Proteins (physiology) Proto-Oncogene Proteins c-mdm2 Transcription, Genetic Tumor Protein p73 Tumor Suppressor Protein p53 (metabolism) Tumor Suppressor Proteins Ubiquitin (metabolism)

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