Dean P. Edwards
Professor
Ph.D., Medical College of Georgia, 1976


dean.edwards@uchsc.edu

Steroid receptors are members of a supergene family of ligand-dependent transcription factors that mediate the effects of steroid hormones on patterns of gene expression in target tissues. This laboratory is involved in studies of the molecular mechanisms by which steroid receptors regulate gene transcription. Current projects address three main research problems.

1) The functional role and mechanism of action of coregulatory proteins that are essential for receptor-mediated gene activation. This includes the chromatin high mobility group proteins (HMG-1 and -2) which are required for high affinity binding of steroid receptors to specific cis-acting hormone response elements on target genes and a novel family of transcriptional coactivators. Coactivators have been implicated to function as bridging proteins between the receptor and the basal transcriptional apparatus and to be involved in targeted remodeling of chromatin structure as a result of their intrinsic histone acetyltransferase enzyme activity.

2) Steroid receptors are phosphoproteins and they undergo increased phosphorylation as an early response to hormone binding. To define a functional role for phosphorylation we have identified multiple serine phosphorylation sites (progesterone-PR receptor), have constructed site-directed mutants and are currently analyzing the mutants for altered receptor function in vivo in gene transfection studies.

3) Synthetic steroid antagonists are important compounds both clinically for treatment of breast cancer and other human diseases, and as probes to study receptor mechanisms. We are also investigating the mechanisms by which different classes of antagonists inactivate steroid receptors.

Recent Publications:

  1. Beck CA, Zhang Y, Weigel N, Edwards DP. Two types of anti-progestins have distinct effects on site-specific phosphorylation of human progesterone receptor. J Biol Chem 271-1209-1217 (1996).
  2. Zhang Y, Beck CA, Clement J, Prendergast P, Yip T, Hutchens W, Harper JW, Edwards DP, Weigel NL. Phosphorylation of human progesterone receptor by cyclin-dependent kinase-2 on three sites that are authentic basal phosphorylation sites in vivo. Mol Endocrinol 11:823-832 (1997).
  3. Tetel MJ, Jung S, Carbajo P, Ladtkow T, Skafar DF, Edwards DP. Hinge and amino-terminal sequences contribute to solution dimerization of human progesterone receptor. Mol Endocrinol 11:1114-1128 (1997).
  4. Gass E, Leonhardt S, Altmann M, Nordeen SK, Edwards DP. The antagonists RU486 and ZK98299 stimulate progesterone receptor binding to DNA in vitro and in vivo but have distinct effects on receptor conformation. Endocrinology 139:1905-1919 (1998).
  5. Boonyaratanakornkit V, Melvin V, Prendergast P, Nordeen SK, Bianchi ME, Allegretto E, Edwards DP. High mobility group chromatin proteins -1 and -2 functionally interact with steroid hormone receptors to enhance their binding to DNA in vitro and transcriptional activity in vivo. Mol Cell Biol 18(8):4471-4487 (1998).
  6. Oñate SA, Tsai MJ, Boonyaratanakornkit V, Edwards DP, O'Malley BW. The steroid receptor coactivator-one contains multiple receptor interacting and activation domains that cooperatively enhances the AF1 and AF2 domains ofsteroid receptors. J Biol Chem 273:12101-12108 (1998).

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