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J. Biol. Chem., Vol. 278, Issue 49, 49196-49202, December 5, 2003

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p73 Is Regulated by Phosphorylation at the G₂/M Transition^*

From the ^aLaboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome "La Sapienza," 00161 Rome, ^dDepartment of Dermatology, University of Rome "Tor Vergata," 00133 Rome, ^eCenter for Evolutionary Genetics, CNR, 00185 Rome, ^fMolecular Oncogenesis Laboratory, Regina Elena Cancer Institute, 00158 Rome, ^hDepartment of Internal Medicine, University of L'Aquila, 67100 L'Aquila, and ⁱDepartment of Internal Medicine, University of Cagliari, 09124 Cagliari, Italy

p73 is a p53 paralog that encodes proapoptotic (transactivation-competent (TA)) and antiapoptotic (dominant negative) isoforms. TAp73 transcription factors mediate cell cycle arrest and/or apoptosis in response to DNA damage and are involved in developmental processes in the central nervous system and the immune system. p73 proteins may also play a role in the regulation of cell growth. Indeed, p73 expression is itself modulated during the cell cycle and TAp73 proteins accumulate in S phase cells. In addition, the function of p73 proteins is also regulated by post-translational modifications and protein-protein interactions in different cellular and pathophysiological contexts. Here we show that p73 is a physiological target of the p34^cdc2-cyclin B mitotic kinase complex in vivo. Both p73 and p73 isoforms are hyperphosphorylated in normal mitotic cells and during mitotic arrest induced by microtubule-targeting drugs. p34^cdc2-cyclin B phosphorylates and associates with p73 in vivo, which results in a decreased ability of p73 to both bind DNA and activate transcription in mitotic cells. Indeed, p73 is excluded from condensed chromosomes in meta- and anaphase, redistributes throughout the mitotic cytoplasm, and unlike p53, shows no association with centrosomes. Together these results indicate that M phase-specific phosphorylation of p73 by p34^cdc2-cyclin B is associated with negative regulation of its transcriptional activating function.

Received for publication, May 10, 2003 , and in revised form, July 29, 2003.

This work is dedicated to our late colleague and friend Franco Tatò.

^* This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (to M. L., G. B., and P. L.) and from MURST-Cofin, Telethon, Istituto Superiore di Sanità-Viral Hepatitis Project, and Schering-Plough (to M. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b These authors contributed equally to this work.

^c Supported by fellowships from the Fondazione A. Cesalpino.

^g Supported by European Community Grant QL61-1999-00273.

^j To whom correspondence should be addressed: Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome La Sapienza, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy. Tel.: 39-06-52662522; Fax: 39-06-4940594; E-mail: levmax{at}tin.it.

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