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J. Biol. Chem., Vol. 280, Issue 34, 30354-30360, August 26, 2005

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A Role of p73 in Mitotic Exit^*

From the ^aLaboratory of Gene Expression, Fondazione Andrea Cesalpino, 00161 Rome Italy, the ^eDepartment of Dermatology, University of Rome "Tor Vergata," 00133 Rome, Italy, the ^fCNR Institute of Molecular Biology and Pathology, Section of Genetics, 00185 Rome, Italy, the ^hMolecular Oncogenesis Laboratory, Regina Elena Cancer Center, 00158 Rome, Italy, the ^jNational Cancer Center, Tokyo 1004-0045, Japan, and the ^kDepartment of Internal Medicine, University of Rome La Sapienza, 00161 Rome, Italy

The p53-related p73 proteins regulate developmental processes, cell growth, and DNA damage response. p73 function is regulated by post-translational modifications and protein-protein interactions. At the G₂/M transition, p73 is phosphorylated at Thr-86 by the p34cdc2/cyclin B complex; this is associated with its exclusion from condensed chromosomes and loss of DNA binding and transcriptional activation ability. Here we showed that p73 hypo-phosphorylated species reappear during mitotic exit, concomitant with p73 relocalization to telophase nuclei and recovered ability to activate transcription. Functional knock-out of p73 gene expression by small interfering RNAs (siRNAs) alters mitotic progression, yielding an increase of ana-telophase cells, the accumulation of aberrant late mitotic figures, and the appearance of abnormalities in the subsequent interphase. This p73 activity at the M-to-G₁ transition is mediated by its transactivating function because expression of the transcription dominant negative mutant p73DD induces the same mitotic exit phenotype. We also found that the cyclin-dependent kinase inhibitor Kip2/p57 gene is a specific target of p73 regulation during mitotic exit and re-entry into G₁. Both knock-out of p73 gene expression by siRNAs and abrogation of p73-dependent transcription by the p73DD mutant abrogate Kip2/p57 increase at the M-to-G₁ transition. Moreover, similar abnormalities (e.g. delay in late mitotic stages with the accumulation of aberrant ana-telophase figures, and abnormalities in the following interphase) are observed in cultures in which the expression of Kip2/p57 is abrogated by siRNAs. These results identify a novel p73-Kip2/p57 pathway that coordinates mitotic exit and transition to G₁.

Received for publication, January 18, 2005 , and in revised form, June 8, 2005.

^* This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro and Ministero dell'Istruzione, dell'Università e della Ricerca-Fondo per gli Investimenti della Ricerca di Base (MIUR-FIRB) (to M. L., G. B., and P. L.), European Community (Grant QL61-1999-00273 to G. B. and Grant LSHC-CT-2004-503576 to M. L. and G. B.), and MIUR-Cofin, Telethon 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 a fellowship from the Fondazione A. Cesalpino.

^d Present address: Muscle Gene Expression Group Laboratory of Muscle Biology, NIAMS, National Institutes of Health, Bethesda, MD 20892.

^g Supported by MIUR-FIRB grant CNRRBAU01CH2M_002.

ⁱ Supported by European Community Grant QL61-1999-00273.

^l To whom correspondence should be addressed. Tel.: 39-06-52662522; Fax: 39-06-52662505; E-mail: levmax{at}tin.it.

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