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J. Biol. Chem., Vol. 280, Issue 2, 1112-1122, January 14, 2005

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Myc Antagonizes Ras-mediated Growth Arrest in Leukemia Cells through the Inhibition of the Ras-ERK-p21^Cip1 Pathway^*

Jose P. Vaqué, Joaquin Navascues¶, Yuzuru Shiio||, Marikki Laiho**, Nuria Ajenjo, Itsaso Mauleon, David Matallanas, Piero Crespo, and Javier León¶¶

From the Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular and ^¶Anatomía y Biología Celular, Unidad de Biomedicina del Consejo Superior de Investigaciones Cientiíficas, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain, the ^||Basic Sciences Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, the ^**Haartman Institute, University of Helsinki, 00014 Helsinki, Finland, and the Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientiíficas, 28029 Madrid, Spain

Even though RAS usually acts as a dominant transforming oncogene, in primary fibroblasts and some established cell lines Ras inhibits proliferation. This can explain the virtual absence of RAS mutations in some types of tumors, such as chronic myeloid leukemia (CML). We report that in the CML cell line K562 Ras induces p21^Cip1 expression through the Raf-MEK-ERK pathway. Because K562 cells are deficient for p15^INK4b, p16^INK4a, p14^ARF, and p53, this would be the main mechanism whereby Ras up-regulates p21 expression in these cells. Accordingly, we also found that Ras suppresses K562 growth by signaling through the Raf-ERK pathway. Because c-Myc and Ras cooperate in cell transformation and c-Myc is up-regulated in CML, we investigated the effect of c-Myc on Ras activity in K562 cells. c-Myc antagonized the induction of p21^Cip1 mediated by oncogenic H-, K-, and N-Ras and by constitutively activated Raf and ERK2. Activation of the p21^Cip1 promoter by Ras was dependent on Sp1/3 binding sites in K562. However, mutational analysis of the p21 promoter and the use of a Gal4-Sp1 chimeric protein strongly suggest that c-Myc affects Sp1 transcriptional activity but not the binding of Sp1 to the p21 promoter. c-Myc-mediated impairment of Ras activity on p21 expression required a transactivation domain, a DNA binding region, and a Max binding region. Moreover, the effect was independent of Miz1 binding to c-Myc. Consistent with its effect on p21^Cip1 expression, c-Myc rescued cell growth inhibition induced by Ras. The data suggest that in particular tumor types, such as those associated with CML, c-Myc contributes to tumorigenesis by inhibiting Ras antiproliferative activity.

Received for publication, August 18, 2004 , and in revised form, October 22, 2004.

^* This work was supported in part by Dirección General de Investigación, Spanish Ministerio de Ciencia y Tecnología Grants SAF02-4193 (to J. L.) and BMC2002-01021 (to P. C.). 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 fellowships from the Spanish Ministerio de Ciencia y Tecnología.

Supported by a fellowship from Fondo de Investigaciones Sanitarias.

^¶¶ To whom correspondence should be addressed: Dept. de Biología Molecular, Facultad de Medicina, Avda Cardenal Herrera Oria s/n, 39011 Santander, Spain. Tel.: 34-942-201952; Fax: 34-942-201945; E-mail: leonj{at}unican.es.

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