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J. Biol. Chem., Vol. 283, Issue 19, 13450-13458, May 9, 2008

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E1a Gene Expression Blocks the ERK1/2 Signaling Pathway by Promoting Nuclear Localization and MKP Up-regulation

IMPLICATION IN v-H-Ras-INDUCED SENESCENCE^*

Juan L. Callejas-Valera¹, Juan Guinea-Viniegra¹², Carmen Ramírez-Castillejo¹, Juan A. Recio, Eva Galan-Moya, Natalia Martinez^¶, Jose M. Rojas^¶, Santiago Ramón y Cajal^||, and Ricardo Sánchez-Prieto³

From the Centro Regional Investigaciones Biomédicas/Facultad de Medicina, Universidad de Castilla la Mancha, Albacete 02006, the Programa de Oncología Médica, Institut de Recerca Vall d'Hebron Hospital, Universitario Vall d'Hebron, Barcelona 08035, the ^¶Unidad de Biología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid 28220, and the ^||Servicio de Anatomía Patológica, Hospital Universitario Vall d'Hebron, Barcelona 08035, Spain

In response to oncogenic signals, cells have developed safe mechanisms to avoid transformation through activation of a senescence program. Upon v-H-Ras overexpression, normal cells undergo senescence through several cellular processes, including activation of the ERK1/2 pathway. Interestingly, the E1a gene from adenovirus 5 has been shown to rescue cells from senescence by a yet unknown mechanism. We investigated whether E1a was able to interfere with the ERK1/2 signaling pathway to rescue cells from v-H-Ras-mediated senescence. Our results show that, E1a overexpression blocks v-H-Ras-mediated ERK1/2 activation by two different and concomitant mechanisms. E1a through its ability to interfere with PKB/Akt activation induces the down-regulation of the PEA15 protein, an ERK1/2 nuclear export factor, leading to nuclear accumulation of ERK1/2. In addition to this, we show that E1a increases the expression of the inducible ERK1/2 nuclear phosphatases (MAPK phosphatases) MKP1/DUSP1 and DUSP5, which leads to ERK1/2 dephosphorylation. We confirmed our observations in the human normal diploid fibroblasts IMR90, in which we could also show that an E1a mutant, unable to bind retinoblastoma protein (pRb), cannot rescue cells from v-H-Ras-induced senescence. In conclusion, E1a is able to rescue from Ras-induced senescence by affecting ERK1/2 localization and phosphorylation.

Received for publication, November 9, 2007 , and in revised form, February 15, 2008.

^* This work was supported by grants from the Fundación Leticia Castillejo Castillo, Conserjería de Educación y Ciencia JCCM Grant PAI07-0012-0393 and Ministerio de Educación y Ciencia Grant SAF 2006/01479 (to R. S. P.), and Ministerio de Educación y Ciencia Grant SAF2006-04247 and ISCIII-RETIC RD06/0020 from the Ministerio de Sanidad y Consumo (to J. M. R.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5.

¹ These authors have contributed equally to this work.

² Present address: Institute of Molecular Pathology, Vienna, Austria.

³ To whom correspondence should be addressed. Tel.: 34-967599200 (ext. 2981); Fax: 34-967599327; E-mail: ricardo.sanchez{at}uclm.es.

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