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Specific Contribution of p19^ARF to Nitric Oxide-Dependent Apoptosis¹

Miriam Zeini^*, Paqui G. Través^*, Raquel López-Fontal^*, Cristina Pantoja, Ander Matheu, Manuel Serrano, Lisardo Boscá^* and Sonsoles Hortelano^2,*

^* Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; and Spanish National Cancer Center, Madrid, Spain

NO is an important bioactive molecule involved in a variety of physio- and pathological processes, including apoptosis induction. The proapoptotic activity of NO involves the rise in the tumor suppressor p53 and the accumulation and targeting of proapoptotic members of the Bcl-2 family, in particular Bax and the release of cytochrome c from the mitochondria. However, the exact mechanism by which NO induces p53 activation has not been fully elucidated. In this study, we describe that NO induces p19^ARF through a transcriptional mechanism. This up-regulation of p19^ARF activates p53, leading to apoptosis. The importance of p19^ARF on NO-dependent apoptosis was revealed by the finding that various cell types from alternate reading frame-knockout mice exhibit a diminished response to NO-mediated apoptosis when compared with normal mice. Moreover, the biological relevance of alternative reading frame to p53 apoptosis was confirmed in in vivo models of apoptosis. Together, these results demonstrate that NO-dependent apoptosis requires, in part, the activation of p19^ARF.

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 This work was funded by the Ministerio de Educación y Ciencia (SAF2002-0083) and by Fundació La Caixa (ONO3-180-2). M.Z. is funded by Community of Madrid; P.G.T. is supported by a Beca de Formación en Investigación fellowship from Instituto de Salud Carlos III; and R.L.-F. is supported by a Formación de Profesorado Universitario fellowship from the Spanish Ministry of Education and Science. S.H. is a Fondo de Investigaciones Sanitarias program investigator and is supported by Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), and Instituto de Salud Carlos III with a project Fondo de Investigaciones Sanitarias (2002/3022) and PI05.0050 (2005).

² Address correspondence and reprint requests to Dr. Sonsoles Hortelano, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029 Madrid, Spain. E-mail address: shortelano{at}cnic.es

³ Abbreviations used in this paper: INK4a, inhibitor of cyclin-dependent kinase 4a; ARF, alternative reading frame; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ATM, ataxia telangiectasia-mutated; ATR, ATM and Rad3 related; cIAP, cellular inhibitors of apoptosis protein; D-GalN, D-galactosamine; GSNO, S-nitrosoglutathione; IAP, inhibitor of apoptosis protein; iNOS, inducible NO synthase; MEF, mouse embryonic fibroblast; PI, propidium iodide; WT, wild type; SIN-1, 3-morpholinosydnonimine.

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