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Molecular and Cellular Biology, August 2005, p. 6937-6947, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.6937-6947.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

p53-Dependent Regulation of Cdc6 Protein Stability Controls Cellular Proliferation{dagger}

Anja Duursma and Reuven Agami*

Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Received 26 January 2005/ Returned for modification 16 March 2005/ Accepted 27 May 2005

Activation of tumor suppressor p53 in response to genotoxic stress imposes cellular growth arrest or apoptosis. We identified Cdc6, a licensing factor of the prereplication complex, as a novel target of the p53 pathway. We show that activation of p53 by DNA damage results in enhanced Cdc6 destruction by the anaphase-promoting complex. This destruction is triggered by inhibition of CDK2-mediated CDC6 phosphorylation at serine 54. Conversely, suppression of p53 expression results in stabilization of Cdc6. We demonstrate that loss of p53 results in more replicating cells, an effect that can be reversed by reducing Cdc6 protein levels. Collectively, our data suggest that initiation of DNA replication is regulated by p53 through Cdc6 protein stability.

* Corresponding author. Mailing address: Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 31 20 512 2079. Fax: 31 20 512 2029. E-mail: r.agami{at}nki.nl.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2005, p. 6937-6947, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.6937-6947.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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