The Role of Progesterone Receptor Phosphorylation in Target Gene Regulation

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DESCRIPTION (provided by applicant): The steroid hormone, progesterone, plays key roles including the growth and development of the mammary glands, uterus, and ovaries. The physiological effects of progesterone occur mainly through its interaction with the specific steroid receptor, progesterone receptor (PR). The target genes for PR have been identified in various tissues, including those implicated in breast cancer. Phosphorylation is an integral regulator of protein/protein interactions, which are required for steroid receptors (SRs), like PR, to recruit coactivators and interact with target genes. Understanding SR function requires the elucidation of how these complex interactions are regulated. The goal of this proposal is to understand how site-specific protein phosphorylation regulates the activity of the PR. The hypothesis is site-specific PR phosphorylation facilitates protein/protein interactions that are essential for the regulation of subsets of PR target genes. In addition, this phosphorylation is an important prerequisite for context and tissue-specific, physiological actions or PR in response to hormone. We have identified the Ser190 phosphorylation sites in human PR and the homologous site in mice, Ser191, and have extensive experience in studying PR actions and the effects of cell signaling on PR. The specific aims are: 1) to determine the mechanism by which Ser190 phosphorylation modulates PR function in human breast cancer cells, 2) to test the concept that selective elimination of a PR phosphorylation site will compromise PR function in vivo in mice, and 3) to perform limited gene expression studies in wild type and PRAIa191 mutant mice. This will be the first test for a role of any steroid receptor phosphorylation in vivo. It is expected that the site-specific phosphorylation of PR at Ser190 is essential for the regulation of a subset of PR target genes in response to hormone. The destruction of the homologous phosphorylation site in mice will verify its importance in vivo. Successful completion of these studies will have a major impact in demonstrating the importance of how PR modifications can affect its function. By increasing our understanding of how PR and other steroid receptors function, we can develop drugs that target certain functions of the specific steroid receptor to treat diseases like breast cancer and uterine cancer without causing harm to other parts of the body.