Recent evidence from the literature and from the applicant's laboratory points toward the physical interaction of estrogen receptor-a (ERa), p53 and hdm2. There are a number of ramifications, real and hypothesized, of this phenomenon. First, p53 down-regulates estradiol (E2)-responsive genes by interfering with the binding of ERa to ERE. Second, ERa in this ternary complex appears to bring about the protection of p53 transcriptional activity from being deactivated by hdm2. Third, this interplay could result in hdm2 regulation of ERa turnover. And fourth, as a consequence, regulated ERa expression may be a method of cellular control of p53 function. Employing transient and stable cell transfections, site directed mutagenesis, GST pull down methodology, ubiquitination assays, and reporter gene transcription assays, studies will be designed to address the following specific aims: Determine the residues involved in mediating the ERa-p53 and ERa-hdm2 binding in order to identify specific mutants of these regulatory proteins useful in examining the biological consequences of these interactions. Examine the biological consequences of the ERa-p53 interaction in breast cancer cells. Examine the functional consequences of the ERa-hdm2 interaction. Explore the possibility that ERbeta performs a function similar to ERa in this regulatory system. These studies will further develop the recently elucidated role of the unliganded ERa in the protection of the tumor suppressor p53 from deactivation by the oncogene hdm2. This tumor suppressor-like activity of ERa is a novel role for the estrogen receptor separate from its classic regulatory function as a ligand inducible transcription factor. The practical significance of these phenomena may be that the ERa-p53 binding protects breast epithelial and endometrial cells from hyperproliferation, which could contribute to malignant transformation, and the interaction of receptor with p53 mutants may play a role in the acquisition of hormone independence by ER positive breast cancer cells.
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