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J. Biol. Chem., Vol. 279, Issue 9, 8076-8083, February 27, 2004
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From the
Biochemistry Laboratory, Instituto Dermopatico Dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," 00133 Rome, Italy, the Medical Research Council Toxicology Unit, University of Leicester, Lancaster Road, Leicester LE1 9HN, United Kingdom, the **Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom, the Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the Department of Cystic Fibrosis, National Heart & Lung Institute, Imperial College, London SW3 6LR, United Kingdom, and the ¶¶Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92037
p73, an important developmental gene, shares a high sequence homology with p53 and induces both G1 cell cycle arrest and apoptosis. However, the molecular mechanisms through which p73 induces apoptosis are unclear. We found that p73-induced apoptosis is mediated by PUMA (p53 up-regulated modulator of apoptosis) induction, which, in turn, causes Bax mitochondrial translocation and cytochrome c release. Overexpression of p73 isoforms promotes cell death and bax promoter transactivation in a time-dependent manner. However, the kinetics of apoptosis do not correlate with the increase of Bax protein levels. Instead, p73-induced mitochondrial translocation of Bax is kinetically compatible with the induction of cell death. p73 is localized in the nucleus and remains nuclear during the induction of cell death, indicating that the effect of p73 on Bax translocation is indirect. The ability of p73 to directly transactivate PUMA and the direct effect of PUMA on Bax conformation and mitochondrial relocalization suggest a molecular link between p73 and the mitochondrial apoptotic pathway. Our data therefore indicate that PUMA-mediated Bax mitochondrial translocation, rather than its direct transactivation, correlates with cell death. Finally, human 
Np73, an isoform lacking the amino-terminal transactivation domain, inhibits TAp73-induced as well as p53-induced apoptosis. The Np73 isoforms seem therefore to act as dominant negatives, repressing the PUMA/Bax system and, thus, finely tuning p73-induced apoptosis. Our findings demonstrate that p73 elicits apoptosis via the mitochondrial pathway using PUMA and Bax as mediators.
Received for publication, July 11, 2003 , and in revised form, October 23, 2003.
* This work was supported by the Medical Research Council and by Telethon Grant E417/bi, Italian Institute for Cancer Research (AIRC) Grant 420, European Union Grant QLGI-1999-00739, a Ministero dell'Istruzione dell'Università e della Ricerca, Ministero della Sanità (MinSan) grant (to G. M.), and Telethon Grant E1257 (to F. B.). 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.
|| Recipient of an Italian Federation for Cancer Research (FIRC) fellowship.
¶ To whom correspondence should be addressed: IDI-IRCCS, Biochemistry Laboratory, c/o Dept. of Experimental Medicine, D26/F153, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Tel.: 39-06-20427299; Fax: 39-06-20427290; E-mail: gerry.melino{at}uniroma2.it.
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