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J. Biol. Chem., Vol. 282, Issue 41, 30285-30294, October 12, 2007

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The RAS-dependent ERF Control of Cell Proliferation and Differentiation Is Mediated by c-Myc Repression^*

From the Medical School, University of Crete and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, 710 03, Greece

The ERF transcriptional repressor is a downstream effector of the RAS/ERK pathway that interacts with and is directly phosphorylated by ERKs in vivo and in vitro. This phosphorylation results in its cytoplasmic export and inactivation, although lack of ERK activity allows its immediate nuclear accumulation and repressor function. Nuclear ERFs arrest cell cycle progression in G₁ and can suppress ras-dependent tumorigenicity. Here we provide evidence that ERF function is mediated by its ability to repress transcription of c-Myc. Promoter reporter assays indicate a DNA binding-dependent and repressor domain-dependent Myc transcriptional repression. Chromatin immunoprecipitations in primary cells suggest that ERF specifically binds on the c-Myc promoter in an E2F4/5-dependent manner and only under conditions that the physiological c-Myc transcription is stopped. Cellular systems overexpressing nuclear ERF exhibit reduced c-Myc mRNA and tumorigenic potential. Elimination of Erf in animal models results in increased c-Myc expression, whereas Erf^-/- primary fibroblasts fail to down-regulate Myc in response to growth factor withdrawal. Finally, elimination of c-Myc in primary mouse embryo fibroblasts negates the ability of nuclear ERF to suppress proliferation. Thus Erf provides a direct link between the RAS/ERK signaling and the transcriptional regulation of c-Myc and suggests that RAS/ERK attenuation actively regulates cell fate.

Received for publication, May 30, 2007 , and in revised form, August 13, 2007.

^* This work was supported by the Greek General Secretariat for Research and Development Grants PENED01 ED486 and PENED03 ED626 and the Greek Ministry of Education Grant PYTHAGORAS II KA2091. 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-S3.

¹ Present address: FacultédeMédecine, Laboratoire d'Histologie, Embryologie, et Cytogénétique, Groupe Hospitalo-Universitaire Caremeau, Place du Professeur Robert Debré, 30029 Nimes Cedex, France.

² To whom correspondence should be addressed: Medical School, University of Crete, Voutes, Heraklion, Crete, 710 03, Greece. Tel.: 30-2810-394537; Fax: 30-2810-394530; E-mail: mavro{at}imbb.forth.gr.

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