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J. Biol. Chem., Vol. 280, Issue 17, 16651-16658, April 29, 2005

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MEK-ERK Signaling Controls Hdm2 Oncoprotein Expression by Regulating hdm2 mRNA Export to the Cytoplasm^*

Monika Phelps, Anna Phillips, Matthew Darley, and Jeremy P. Blaydes

From the Cancer Sciences Division, School of Medicine, University of Southampton, MP 824, Southampton General Hospital, Southampton SO16 6YD, United Kingdom

The physical and functional interaction between the transcription factor p53 and its negative regulatory partner protein Hdm2 (Mdm2 in mouse) is a key point of convergence of multiple signaling pathways that regulates cell proliferation and survival. hdm2 mRNA transcription is induced by p53, forming the basis of an auto-regulatory feedback loop. Growth and survival factor-activated Ras-Raf-MEK-ERK signaling can also regulate Hdm2 expression independently of p53, contributing to the pro-survival effect of these factors. In murine fibroblasts, this occurs through the regulation of mdm2 mRNA transcription. Here we show that, in human breast cancer epithelial cells, MEK-dependent regulation of Hdm2 expression also occurs at a post-transcriptional level. Pharmacological blockade of MEK activity in T47D cells inhibits Hdm2 protein synthesis by 80–90%. This occurs in the absence of changes in the expression of the major hdm2-P1 mRNA transcript and only an 40% reduction in hdm2-P2 transcript levels. The amounts of both transcripts that are associated with polyribosomes and are, hence, being actively translated are reduced by >80% by the MEK inhibitor, U0126. We show here that this is due to the inhibition of hdm2 mRNA export from the nucleus when MEK activity is inhibited. In MCF-7 breast cancer cells that express wild-type p53, Hdm2 is required to suppress p53-dependent transcription when MEK kinase is active. Regulation of the nuclear export of hdm2 mRNA provides, therefore, a mechanism whereby mitogen-stimulated cells avoid p53-dependent cell cycle arrest or apoptosis by maintaining the dynamic equilibrium of the Hdm2-p53 feedback loop.

Received for publication, November 1, 2004 , and in revised form, February 16, 2005.

^* This work was supported by Association for International Cancer Research Grants 01-070 and 04-422 (to J. P. B.). 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.

To whom correspondence should be addressed. Tel.: 44-23-8079-4582; Fax: 44-23-8079-5152; E-mail: j.p.blaydes{at}soton.ac.uk.

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