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J. Biol. Chem., Vol. 282, Issue 42, 31060-31067, October 19, 2007

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Ing1 Mediates p53 Accumulation and Chromatin Modification in Response to Oncogenic Stress^*

María Abad¹, Camino Menéndez¹², Annette Füchtbauer, Manuel Serrano^¶, Ernst-Martin Füchtbauer, and Ignacio Palmero³

From the Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28029 Madrid, Spain, the Department of Molecular Biology, Aarhus University, DK-8000 Aarhus, Denmark, and ^¶Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain

ING proteins are putative tumor suppressor proteins linked to the p53 pathway and to the chromatin modification machinery. Here we have analyzed the role of the products of the murine Ing1 locus in cellular tumor-protective responses, using mouse primary fibroblasts where the Ing1 locus has been inactivated by the integration of a geo cassette. We show that Ing1-deficient mouse embryonic fibroblasts display a defective senescence-like antiproliferative response against oncogenic Ras, affecting several senescence-specific markers. This phenotype is accompanied by a reduced accumulation of p53, which can be explained by the reduced basal p53 protein stability in the Ing1-deficient background. Ing1 deficiency also results in defects in the appearance of heterochromatic marks upon expression of oncogenic Ras, suggestive of impaired heterochromatin formation during oncogene-induced senescence. Our results support an important role for the Ing1 locus in protection against oncogenic stress in vivo, both as a mediator of p53 activation and as a regulator of chromatin remodeling processes.

Received for publication, February 23, 2007 , and in revised form, August 6, 2007.

^* This work was supported in part by Grant BFU-06-10882 from the Spanish Ministry of Education, the FMMA Foundation, the Cooperative Cancer Network of the Spanish Ministry of Health (to I. P.), Grant DP00086 from the Danish Cancer Society, Grant 21-03-0591 from the Danish Research Council (to E.-M. F.), and European Union Grant INTACT (to M. S.). 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-S4.

¹ Both authors contributed equally to this work.

² Recipient of a predoctoral fellowship from the Regional Government of Madrid.

³ To whom correspondence should be addressed: Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier, 4, E-28029 Madrid, Spain. Tel.: 34-91-585-4491; Fax: 34-91-585-4401; E-mail: ipalmero{at}iib.uam.es.

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