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J. Biol. Chem., Vol. 278, Issue 42, 41316-41325, October 17, 2003

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v-SRC Specifically Regulates the Nucleo-cytoplasmic Delocalization of the Major Isoform of TEL (ETV6)^*

Rodolphe G. Lopez , Clémence Carron  and Jacques Ghysdael ¶

From the CNRS UMR146-Institut Curie, Centre Universitaire, Bat. 110, 91405 Orsay, France

TEL is a frequent target of chromosomal translocations in human cancer and an alleged tumor suppressor gene. TEL encodes two isoforms: a major TEL-M1 isoform as well as TEL-M43, which lacks the first 42 amino acid residues of TEL-M1. Both isoforms are potent transcriptional repressors that can inhibit RAS-induced transformation. Here we show that the v-SRC proteintyrosine kinase relieves the repressive activity of TEL-M1, an activity that is associated with the v-SRC-induced delocalization of TEL-M1 from the nucleus to the cytoplasm. TEL-M1 delocalization requires the kinase activity of v-SRC and is not induced by oncogenic RAS or AKT. Cytoplasmic delocalization of TEL-M1 in response to v-SRC critically depends upon its unique amino-terminal domain (SRCD domain) because (i) v-SRC did not inhibit the repressive properties of TEL-M43, nor affected TEL-M43 nuclear localization; (ii) fusion of the first 52 amino acid residues of TEL-M1 to FLI-1, an ETS protein insensitive to v-SRC-induced delocalization, is sufficient to confer v-SRC-induced delocalization to this TEL/FLI-1 chimeric protein. The v-SRC-induced nucleo-cytoplasmic delocalization of TEL-M1 does not involve phosphorylation of the SRCD and does not require TEL self-association and repressive domains. Finally, enforced expression of the v-SRC-insensitive TEL-M43, but not of TEL-M1, inhibits v-SRC-induced transformation of NIH3T3 fibroblasts. These results identify a regulatory domain in TEL that specifically impinges on the subcellular localization of its major TEL-M1 isoform. They, furthermore, indicate that inhibition of TEL-M1 nuclear function is required for v-SRC to induce cellular transformation.

Received for publication, June 18, 2003 , and in revised form, July 30, 2003.

^* This work was supported in part by grants from the Ligue Nationale Contre le Cancer (Equipe labelisée), Fondation de France, the European Union and funds from the Institut Curie, and Centre National de la Recherche Scientifique (CNRS) (to J. G.). 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.

Supported by a pre-doctoral fellowship from the Ligue Nationale Contre le Cancer and Société Française d'Hématologie. Present address: EMBL-Mouse Biology Programme, Via Ramarini, Monterotondo, Italy.

Present address: CNRS UMR7622, Université Pierre et Marie Curie, 75005 Paris, France.

^¶ To whom correspondence should be addressed: CNRS UMR146-Institut Curie, Centre Universitaire, Bat. 110, 91405 Orsay, France. Tel.: 33-1-69-86-31-52; Fax: 33-1-69-07-45-25; E-mail: Jacques.Ghysdael{at}curie.u-psud.fr.

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