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Differential Regulation of Estrogen Receptor Turnover and Transactivation by Mdm2 and Stress-Inducing Agents

¹ Institut National de la Santé et de la Recherche Médicale U540; ² Université Montpellier I; and ³ Institut de Génétique Moléculaire de Montpellier, Montpellier, France

Requests for reprints: Vincent Cavaillès, Institut National de la Sante et de la Recherche Medicale U540, 60 rue de Navacelles, Montpellier, F-34090 France. Phone: 33-4-67-61-24-05; Fax: 33-4-67-61-37-87; E-mail: v.cavailles{at}valdorel.fnclcc.fr.

In mammalian cells, the level of estrogen receptor (ER) is rapidly decreased upon estrogen treatment, and this regulation involves proteasome degradation. Using different approaches, we showed that the Mdm2 oncogenic ubiquitin-ligase directly interacts with ER in a ternary complex with p53 and is involved in the regulation of ER turnover (both in the absence or presence of estrogens). Several lines of evidence indicated that this effect of Mdm2 required its ubiquitin-ligase activity and involved the ubiquitin/proteasome pathway. Moreover, in MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) or treatment with RITA (which inhibits the interaction of p53 with Mdm2) stabilized ER and abolished its 17ß-estradiol–dependent turnover. Interestingly, our data indicated that ligand-dependent receptor turnover was not required for efficient transactivation. Altogether, our results indicate that the Mdm2 oncoprotein and stress-inducing agents complexly and differentially regulate ER stability and transcriptional activity in human cancer cells. [Cancer Res 2007;67(11):5513–21]

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