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

Oncogene volume 22, pages 1678–1687 (2003)Cite this article

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.

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Acknowledgements

We thank J Kwak for proofreading the manuscript, H Nojima for cyclin G constructs, G Lozano for Mdm2−/− MEF and T Ouchi for helpful discussion. This work was supported by the Charlotte Geyer Foundation and NIH Grants CA85681, CA78356 and CA80058.

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Authors and Affiliations

  1. Hematology and Oncology Division, Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02115, MA, USA

    Takao Ohtsuka, Yohji A Minamishima, Akihide Ryo & Sam W Lee

  2. Department of Neurology, University of Massachusetts Medical School and Memorial Health Care Center, Worcester, 01605, MA, USA

    Hoon Ryu

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  1. Takao Ohtsuka
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Correspondence to Sam W Lee.

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Ohtsuka, T., Ryu, H., Minamishima, Y. et al. Modulation of p53 and p73 levels by cyclin G: implication of a negative feedback regulation. Oncogene 22, 1678–1687 (2003). https://doi.org/10.1038/sj.onc.1206306

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