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J. Biol. Chem., Vol. 282, Issue 48, 34938-34944, November 30, 2007

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Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence^*

From the Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada

Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16^INK4a, which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence.

Received for publication, August 23, 2007 , and in revised form, October 2, 2007.

^* This work was supported in part by the Canadian Institutes of Health Research (to G. F.) and a fellowship from the Fonds de Recherche en Santé du Québec (to F. A. M.). 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 "Experimental Procedures," Figs. 1 and 2, and references.

¹ To whom correspondence should be addressed: Dépt. de Biochimie, Université de Montréal, E-515, C. P. 6128, Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada. Tel.: 514-343-7571; Fax: 514-343-2210; E-mail: g.ferbeyre{at}umontreal.ca.

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