In mammalian cells, the level of estrogen receptor A (ERA) is rapidly decreased upon estrogen treatment, and this regulation involves proteasome degradation. Using different approaches, we showed that the Mdm2 oncogenic ubiquitinligase directly interacts with ERA in a ternary complex with p53 and is involved in the regulation of ERA 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 ERA and abolished its 17B-estradioldependent 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 ERA stability and transcriptional activity in human cancer cells. [Cancer Res 2007;67(11):5513-21]
We have investigated the effects of receptor-interacting protein 140 (RIP140) on transcriptional regulation by estrogen receptor-related receptors (ERRs). We first show that RIP140 inhibits transactivation by ERRalpha, beta, and gamma on natural or artificial reporter genes containing different types of response elements. This repression correlates with a strong in vitro binding between several regions of RIP140 and the three ERR isoforms. Surprisingly, although RIP140 inhibits transactivation of the thyroid hormone receptor-alpha gene by ERRbeta, it significantly increases its regulation by ERRalpha and ERRgamma. Mutagenesis and transient transfections in SL2 cells indicate that thyroid hormone receptor-alpha promoter expression involved Sp1 sites. In support of this observation, we demonstrate that RIP140 also positively regulates ERRs transactivation of other known Sp1 targets such as the p21 gene. This effect requires the two proximal Sp1 binding sites of the promoter and is partially dependent on the activation function 2 domain of ERRs. Finally, we provide evidences for a role of histone deacetylases in the regulation of p21 promoter by RIP140. Altogether, these data indicate that RIP140 differentially regulates ERR activity depending on the target sequence on the promoters.
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