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B in Leukemic T Cells and Is Essential for Their Growth In Vivo1
* Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 5535, Montpellier, France;
Laboratoire de Virologie Moleculaire, Institut de Génétique Humaine, Centre National de la Recherche Scientifique Unité Propre de Recherche 1142, Montpellier, France;
Centro de Biología Molecular, Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Madrid, Spain; and
Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas-Universidad de Salamanca, Salamanca, Spain
MAPK cascades play a central role in the cellular response to the environment. The pathway involving the MAPK ERK5 mediates growth factor- and stress-induced intracellular signaling that controls proliferation or survival depending upon the cell context. In this study, we show that reducing ERK5 levels with a specific small hairpin RNA 5 (shERK5) reduced cell viability, sensitized cells to death receptor-induced apoptosis, and blocked the palliative effects of phorbol ester in anti-Fas Ab-treated cells. shERK5 decreased nuclear accumulation of the NF-
B p65 subunit, and conversely, ectopic activation of ERK5 led to constitutive nuclear localization of p65 and increased its ability to trans activate specific reporter genes. Finally, the T lymphoma cell line EL-4, upon expression of shERK5, proliferated in vitro, but failed to induce s.c. tumors in mice. Our results suggest that ERK5 is essential for survival of leukemic T cells in vivo, and thus represents a promising target for therapeutic intervention in this type of malignancy.
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 supported by the French Association pour la Recherche sur le Cancer (to M.V. and R.A.H.); Fondation de France (to M.V.); a Marie Curie International Reintegration Grant (to M.V.); and fellowships from La Ligue Contre le Cancer Department de l’Herault (to S.K.), Region Languedoc-Rousillon (to S.C.), and Comite National (to J.G.).
2 Address correspondence and reprint requests to Dr. Martin Villalba, Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 5535, Institut Fédératif de Recherche 122, 1919 Route de Mende, 34293 Montpellier, France. E-mail address: martin.villalba{at}igmm.cnrs.fr
3 Abbreviations used in this paper: IGF, insulin-like growth factor; CHX, cycloheximide; DN, dominant negative; FSC, forward scatter; SSC, side scatter; HA, hemagglutinin; IKK, IB kinase; MEF, myocyte enhancer factor; PKC, protein kinase C; RSK1, ribosomal S6 kinase 1; shERK5, small hairpin RNA ERK5; wt, wild type.
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