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J. Biol. Chem., Vol. 279, Issue 31, 32813-32823, July 30, 2004

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Subcellular Localization Determines the Protective Effects of Activated ERK2 against Distinct Apoptogenic Stimuli in Myeloid Leukemia Cells^*

Nuria Ajenjo, Estela Cañón¶, Isabel Sánchez-Pérez||, David Matallanas**, Javier León, Rosario Perona, and Piero Crespo

From the Instituto de Investigaciones Biomédicas, CSIC, Madrid 28029 and Departamento de Biología Molecular, Unidad de Biomedicina de la Universidad de Cantabria-CSIC, Santander 39011, Spain

ERKs, mitogen-activated protein kinases, are well characterized as key mediators in the conveyance of signals that promote cell survival in cells of hemopoietic origin, a key factor in the upbringing of leukemogenesis. It is also well known that ERKs phosphorylate a wide array of substrates distributed throughout distinct cellular locations such as the nucleus, cytoplasm, and cell periphery, but the relative contribution of these compartmentalized signal components to the overall survival signal generated by activation of ERKs has yet to be established. To this end, we have utilized constitutively activated forms of ERK2, whose expression is restricted to the nucleus or to the cytoplasm, to investigate the consequences of compartmentalized activation of ERK in the survival of chronic myelogenous leukemia cells subjected to distinct apoptogenic stimuli. We show that cytoplasmic ERK2 activity protected against apoptosis caused by prolonged serum starvation, whereas ERK2 activation restricted to the nucleus antagonized apoptosis induced by the Bcr-Abl inhibitor STI571. On the other hand, neither cytoplasmic nor nuclear ERK2 activities were effective in counteracting apoptosis induced by UV light. These results demonstrate that the protective effects of ERK2 against defined apoptogenic stimuli are strictly dependent on the cellular localization where ERK activation takes place. Furthermore, we present evidence suggesting that the complex IB-NFB participates on ERK2-mediated survival mechanisms, in a fashion dependent on the cellular location where ERK2 is active and on the causative apoptogenic stimulus.

Received for publication, December 12, 2003 , and in revised form, May 25, 2004.

^* This work was supported by a grant from Fundación Marcelino Botín, Spanish Ministry of Education Grants BMC2002-0102 (to P. C.) and SAF02-4193 (to J. L.), and by Spanish Ministry of Health Grant FIS PI020774 (to R. P.). 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.

^¶ Postdoctoral fellow of the Association for International Cancer Research.

^|| Postdoctoral fellow of the Comunidad de Madrid.

^** Postdoctoral fellow of the CSIC I3P program.

To whom correspondence should be addressed: Instituto de Investigaciones Biomédicas, CSIC, Unidad de Biomedicina de la Universidad de Cantabria-CSIC, Departamento de Biologiéa Molecular, Facultad de Medicina, C/Cardenal Herrera Oria s/n., Santander 39011, Spain. Tel.: 34-942-200959; Fax: 34-942-201945; E-mail: pcrespo{at}iib.uam.es.

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