The long term goal of this project is to determine the physiological roles for phosphorylation of steroid receptors. As a model, our studies focus on the human progesterone receptor (hPR). In the previous grant period, eight phosphorylation sites were identified in hPR. This information will be utilized to determine the functions of the individual sites.
The specific aims for this grant period are 1. To mutate each hPR phosphorylation site and to determine the effects of these changes in vivo on protein expression, phosphorylation of other sites (hierarchal phosphorylation) and transcriptional activity. We will determine whether the phosphorylation of hPR is hierarchical and with transcriptional activation assays as an endpoint will determine which sites affect overall activity in vivo. 2. To determine mechanistically how phosphorylation sites affect specific factions of PR. Based on the results in Aim #1 selected analyses of specific receptor function (interaction with heat shock proteins, receptor dimerization, DNA binding and interaction with other factors) will be performed to determine the specific roles for each phosphorylation site. 3. To determine whether phosphorylation contributes to functional differences between the A and B forms of progesterone receptor. The finding that PR-B is a strong activator and PR-A can act as a repressor suggests very different functions for these proteins. That there are phosphorylations unique to PR-B suggests that phosphorylation plays a role in these unique functions. 4. To identify kinases that phosphorylate purified hPR in vitro on authentic phosphorylation sites and to use in vitro phosphorylated receptor to study the role of phosphorylation in receptor function. Purified receptor phosphorylated on specific sites or subsets of sites will be used to quantify the effects of these phosphorylations on binding to DNA using fluorescence anisotropy (FAS). That antagonists can act as agonists when kinase activity is altered has important implications in determining the mechanism by which hormone resistance occurs in breast cancer. Phosphorylated receptor will be used in a differential screen to identify proteins that interact specifically with the PR-B specific region of the receptor and are potential mediators of the PR-B specific antagonist/agonist switch in response to activators of Protein Kinase A.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Reproductive Endocrinology Study Section (REN)
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Mohla, Suresh
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Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Treviño, Lindsey S; Bolt, Michael J; Grimm, Sandra L et al. (2016) Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK. Mol Endocrinol 30:158-72
Grimm, Sandra L; Ward, Robert D; Obr, Alison E et al. (2014) A role for site-specific phosphorylation of mouse progesterone receptor at serine 191 in vivo. Mol Endocrinol 28:2025-37
Moore, Nicole L; Edwards, Dean P; Weigel, Nancy L (2014) Cyclin A2 and its associated kinase activity are required for optimal induction of progesterone receptor target genes in breast cancer cells. J Steroid Biochem Mol Biol 144 Pt B:471-82
Treviño, Lindsey S; Bingman 3rd, William E; Edwards, Dean P et al. (2013) The requirement for p42/p44 MAPK activity in progesterone receptor-mediated gene regulation is target gene-specific. Steroids 78:542-7
Treviño, Lindsey S; Weigel, Nancy L (2013) Phosphorylation: a fundamental regulator of steroid receptor action. Trends Endocrinol Metab 24:515-24
Moore, Nicole L; Weigel, Nancy L (2011) Regulation of progesterone receptor activity by cyclin dependent kinases 1 and 2 occurs in part by phosphorylation of the SRC-1 carboxyl-terminus. Int J Biochem Cell Biol 43:1157-67
Ward, Robert D; Weigel, Nancy L (2009) Steroid receptor phosphorylation: Assigning function to site-specific phosphorylation. Biofactors 35:528-36
Weigel, N L; Moore, N L (2007) Cyclins, cyclin dependent kinases, and regulation of steroid receptor action. Mol Cell Endocrinol 265-266:157-61
Moore, Nicole L; Narayanan, Ramesh; Weigel, Nancy L (2007) Cyclin dependent kinase 2 and the regulation of human progesterone receptor activity. Steroids 72:202-9
Weigel, Nancy L; Moore, Nicole L (2007) Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol 21:2311-9

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