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J. Biol. Chem., Vol. 280, Issue 40, 34159-34169, October 7, 2005

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Full-length p73 Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells^*

Ulrika Nyman, Agnieszka Sobczak-Pluta, Pinelopi Vlachos, Thomas Perlmann, Boris Zhivotovsky, and Bertrand Joseph1

From the Karolinska Institutet, Institute of Environmental Medicine, S-171 77 Stockholm, Sweden and The Ludwig Institute for Cancer Research, S-171 77 Stockholm, Sweden

The p73 gene, a member of the p53 family, encodes several variants through differential splicing and use of alternative promoters. At the NH₂ terminus, two different promoters generate the full-length and the N isoforms, with or without the transactivating domain. At the COOH terminus, seven isoforms generated through alternative splicing have been cloned. Previous studies have demonstrated that Np73 isoforms exert a dominant-negative effect on p73 by blocking their transactivation activity and hence the ability to induce apoptosis. Considerable efforts are made to identify the functional diversity of the COOH-terminal p73 variants. In this study, we found that p73 inhibited drug-induced apoptosis in small cell lung carcinoma cells, whereas p73 promoted it. p73 prevented Bax activation, mitochondrial dysfunction, and caspase activation. In addition, p73 was also able to reduce apoptosis induced by the BH3-only protein PUMA (p53 up-regulated modulator of apoptosis). Furthermore, we discovered that p73 is able to inhibit the pro-apoptotic effect of p73, demonstrating the existence of equilibrium between these two p73 isoforms. In conclusion, the reported overexpression of p73 in certain tumor types, and our findings that p73 exerts anti-apoptotic functions, indicate a potential oncogenic activity for p73.

Received for publication, January 12, 2005 , and in revised form, June 30, 2005.

^* This work was supported by Swedish Research Council Grants K2004-32XD-15127-01A and 31X-02471-37A, Swedish Cancer Society Grants 4868-B03-01XAB and 3829-B04-09XAC, the Åke Wiberg Foundation, the Swedish Medical Society, and European Commission Grant QLK3-CT-2002-01956. 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.

¹ To whom correspondence should be addressed: Karolinska Institutet, Institute of Environmental Medicine, Box 210, S-171 77 Stockholm, Sweden. Tel.: 46-8-524-875-56; Fax: 46-8-32-90-41; E-mail: Bertrand.Joseph{at}imm.ki.se.

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