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J. Biol. Chem., Vol. 280, Issue 7, 5945-5959, February 18, 2005

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E1A Activates Transcription of p73 and Noxa to Induce Apoptosis^*

Marcella Flinterman¶, Lars Guelen¶, Samira Ezzati-Nik, Richard Killick||, Gerry Melino**, Kazuya Tominaga, Joe S. Mymryk, Joop Gäken¶¶, and Mahvash Tavassoli||||

From the Head and Neck Oncology Group, Guy's King's & St. Thomas's School of Dentistry and the ^¶¶Department of Hematological and Molecular Medicine, King's College London, London SE5 9NU, United Kingdom, the ^||Department of Neuroscience, Institute of Psychiatry, London SE5 8AF, United Kingdom, the ^**Instituto Dermopatico Immacolata-Instituto Ricerca Clinica Carattere Scientifico Laboratory, Department of Experimental Medicine and Biochemical Sciences, University of Rome, 00133 Rome, Italy and the MRC Toxicology Unit, Leicester LE1 9HN, United Kingdom, the Department of Oral Pathology, Osaka Dental University, Osaka 573-1121, Japan, and the Departments of Oncology and Microbiology & Immunology, University of Western Ontario, London Regional Cancer Center, London, Ontario N6A 4L6, Canada

p73, a member of the p53 family of proteins, transcriptionally activates a number of genes involved in the control of cell cycle and apoptosis. Overexpression of p73 was detected in a large number of primary head and neck cancers, and in the established cell lines examined, these all contained inactivating p53 mutations. The significance of p73 overexpression in the pathogenesis of head and neck cancer is currently unclear. We have shown that the expression of adenovirus 5 E1A in a panel of head and neck cancer cell lines induces apoptosis independently of their p53 status. In this study we examined the role of p73 and its transcriptional targets in E1A-mediated induction of apoptosis. E1A expression resulted in significant activation of the TAp73 promoter but had no effect on the alternative, Np73 promoter. E1A also increased expression of endogenous TAp73 mRNA and protein. E1A mutants lacking the p300- and/or pRB-binding sites showed reduced ability to activate the TAp73 promoter. Additionally, mutations in the E2F1-binding sites in the TAp73 promoter impaired activation by E1A. Importantly, expression of the 13S isoform of E1A substantially induced the p53 apoptotic target Noxa in several p53-deficient cancer cell lines. Our results indicate that E1A activation of p73 and the p53 apoptotic target Noxa can occur in the absence of a functional p53. This activation is likely to play a key role in the mechanism of p53-independent apoptosis induced by E1A in some cancers and may provide an avenue for future cancer therapies.

Received for publication, June 15, 2004 , and in revised form, November 27, 2004.

^* This work was partly supported by Biotechnology and Biological Sciences Research Council Grant 47/GTH12530. 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.

Supported by the Guy's King's & St. Thomas's Dental Institute.

^¶ These authors contributed equally to this work.

^|||| To whom correspondence should be addressed: Head and Neck Oncology Group, Dept. of Oral Medicine and Pathology, King's College London, 123 Coldharbour Lane, London SE5 9NU, UK. Tel.: 44-20-7848-5913; Fax: 44-20-7733-3877; E-mail: mahvash.tavassoli{at}kcl.ac.uk.

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