Physiology and Pharmacology : Edwin R. Sanchez

Professor Telephone: (419) 383-4182, 383-4187 FAX: (419) 383-2871 e-mail: Edwin.Sanchez@utoledo.edu For more information on Steroid Receptor Research, see:  Steroid Receptor Associated Proteins Resource or Glucocorticoid Receptor Resource

Training

• B.A., Biology, 1974, Wesleyan University
• Ph.D., Human Genetics, 1983, University of Michigan

Appointments

• Postdoctoral Fellow, Department of Human Genetics, University of Michigan, 1983-1984
• Research Fellow, Department of Pharmacology, University of Michigan, 1984- 1987
• Research Investigator, Department of Pharmacology, University of Michigan, 1987-1989
• Assistant Research Scientist, Department of Pharmacology, University of Michigan, 1989
• Assistant Professor of Pharmacology and Therapeutics, Medical College of Ohio, 1989-1994
• Associate Professor of Pharmacology and Therapeutics, Medical College of Ohio, 1994-2000
• Professor of Physiology, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, 2000-present
• Assistant Director, Center for Diabetes and Endocrine Research (CeDER), University of Toledo College of Medicine, Health Science Campus, 2006-

Research Interests:

Regulation of steroid hormone receptors, with emphasis on the convergence of the heat shock, immunophilin and glucocorticoid receptor signal pathways.

Steroid hormones are a large class of cholesterol-derived molecules which serve to control the functional states of a variety of cells and target tissues. These hormones include progestins, estrogens, androgens, mineralocorticoids and glucocorticoids. Recent applications of molecular biology techniques have shown that steroid hormones act by binding to intracellular receptor proteins, which in turn serve to regulate specific gene expression by enhancing or repressing mRNA transcription. The central thrust of my research program is to understand the molecular mechanism by which glucocorticoid hormone causes the glucocorticoid receptor (GR) to be transformed from an inactive, non-DNA-binding state to its transcriptionally active form.

Over the past years, my contributions and those of other laboratories have led to the following model of glucocorticoid receptor action. The untransformed GR is localized to the cytoplasm of cells as a large heteromeric complex which contains one steroid-binding subunit (GR), two molecules of the 90-kDA heat shock protein (hsp90), and one molecule of a 56-kDa heat shock protein (hsp56) that is also an immunophilin capable of binding the immunosuppressive drugs FK506 and rapamycin. Upon binding of hormone, the GR dissociates from the complex and then rapidly translocates to the nucleus (by an unknown process) where it dimerizes and binds to glucocorticoid response elements (GREs) which serve as upstream enhancers of mRNA transcription for glucocorticoid-responsive genes.

The presence within GR complexes of both heat shock and immunophilin proteins, both of which have potential calmodulin binding sites, has led our laboratory to focus on the following major questions. What are the roles of the heat shock proteins in generating or maintaining the untransformed receptor complex? What is the relationship of the cellular heat shock response or immunophilin signal pathway to steroid receptor action? Is there a role for calmodulin in the GR signal pathway? These questions are currently being pursued using a combination of molecular, biochemical and immunological techniques.

Representative Publications

• Sánchez E.R. (1990): Hsp56: a novel heat shock protein associated with untransformed steroid-receptor complexes. J. Biol. Chem. 265:22067-22070.
• Sánchez E.R. (1992): Heat shock induces translocation to the nucleus of the unliganded glucocorticoid receptor. J. Biol. Chem. 267: 17-20.
• Ning Y.-M. and Sánchez E.R. (1993): Potentiation of glucocorticoid receptor-mediated gene expression by the immunophilin ligands FK506 and rapamycin. J. Biol. Chem. 268: 6073-6076.
• Sánchez E.R., Hu J.-L., Zhong S., Shen, P., Greene, M.J. and Housley P.R. (1994): Potentiation of glucocorticoid receptor-mediated gene expression by heat and chemical shock. Mol. Endocrinol. 8: 408-421.
• Ning Y.-M. and Sánchez E.R. (1995): Stabilization in vitro of the untransformed glucocorticoid receptor complex of S49 lymphocytes by the immunophilin ligand FK506. J. Steroid Biochem. Mol. Biol. 52: 187-194.
• Ning Y.-M. and Sánchez E.R. (1995): Evidence for a functional interaction between calmodulin and the glucocorticoid receptor. Biochem. Biophys. Res. Commun. 208: 48-54.
• Renoir J.M., Mercier-Bodard C., Hoffman K., Le Bihan S., Ning Y.-M., Sánchez E.R., Handschumacher E. and Baulieu E.-E. (1995): Cyclosporin A, like FK506, potentiates dexamethasone-induced MMTV-CAT activity in LMCAT cells: A possible role for different heat shock protein-binding immunophilins (HBIs) in glucocorticoid receptor-mediated gene expression. Proc. Natl. Acad. Sci. 92:4977-4981.
• Ning Y.-M. and Sánchez E.R. (1996): In vivo evidence for the generation of a glucocorticoid receptor-hsp90 complex incapable of binding hormone by the calmodulin antagonist phenoxybenzamine. Mol. Endocrinol. 10:14-23.
• Hu, J.-L., Guan, X.-J., and Sánchez, E.R. (1996): Enhancement of glucocorticoid receptor-mediated gene expression by cellular stress: evidence for the involvement of a heat shock-initiated factor or process during recovery from stress. Cell Stress & Chaperones 1:197-205.
• Martinez, E., Moore, D.D., Keller, E., Pearce, D., Robinson, V., MacDonald, P.N., Simons, S.S., Sánchez, E.R., and Danielsen, M. (1997): The nuclear receptor resource project. Nucleic Acids Research 25:163-165.
• Martinez, E., Moore, D.D., Keller, E., Pearce, D., Vanden Heuvel, J.P., Robinson, V., Gottlieb, B., MacDonald, P.N., Simons, S.S., Sánchez, E.R., and Danielsen, M. (1998): The nuclear receptor resource: A growing family. Nucleic Acids Research 26:239-241.
• Li, D., Li Calzi, S., and Sánchez, E.R. (1999): Inhibition of heat shock factor activity prevents heat shock potentiation of glucocorticoid receptor-mediated gene expression. Cell Stress & Chaperones 4:223-234.
• Li, D.P., Periyasamy, S., Jones, T.J., and Sanchez, E.R. (2000): Heat and chemical shock potentiation of glucocorticoid receptor transactivation requires Heat Shock Factor (HSF) activity. modulation of HSF by vanadate and wortmannin. J. Biol. Chem. 275: 26058-26065.
• Morishima, Y., Murphy, P.J., Li, D.P., Sanchez, E.R., and Pratt, W.B. (2000): Stepwise assembly of glucocorticoid receptor.hsp90 heterocomplex resolves two sequential ATP-dependant events involving first hsp70 and then hsp90 in opening of the steroid binding pocket. J. Biol. Chem. 275: 18054-18060.
• Wadekar, S., Li, D., Periyasamy, S., and Sanchez, E.R. (2001) Inhibition of heat shock transcription factor by glucocorticoid receptor. Mol. Endocrinol. 15:1396-1410.
• Li Calzi, S., Periyasamy, S., Li, D., and Sanchez, E.R. (2002) Vanadate increases glucocorticoid receptor-mediated gene expression: a novel mechanism for potentiation of a steroid receptor. J. Steroid Biochem. Mol. Biol. 80:35-47.
• Davies, T.H., Ning, Y-M., and Sanchez, E.R. (2002) A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J. Biol. Chem. 277:4597-4600.
• Periyasamy, S. and Sanchez, E.R. (2002) Antagonism of glucocorticoid receptor transactivity and cell growth inhibition by transforming growth factor-ß through AP-1-mediated transcriptional repression. Int. J. Biochem. Cell Biol. 34:1571-1585.
• Wadekar, S., Li, D., and Sanchez, E.R. (2004) Agonist-activated glucocorticoid receptor inhibits binding of heat shock factor 1 to the Hsp70 promoter in vivo. Mol. Endocrinol. 18:500-508.
• Periyasamy, S., Warrier, M., Tillekeratne, M.P., Shou, W., and Sanchez, E.R.  (2007)  The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms.  Endocrinology. 148(10):4716-4726.
• Jones, T., Li, D., Wolf, I.M., Wadekar, S., Periyasamy, S., and Sanchez, E.R. (2004) Enhancement of glucocorticoid receptor-mediated gene expression by constitutively-active heat shock factor 1. Mol. Endocrinol. 18:509-520.
• Davies, T. and Sanchez, E.R. (2005) FKBP52: An FK506-binding tetratricopeptide repeat protein. "Molecules in Focus". Int. J. Biochem. Cell. Biol. 37:42-47.
• Davies, T.H., Ning, Y.M., and Sanchez, E.R. (2005) Differential control of glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506. Biochemistry 15:2030-2038.
• Li, D. and Sanchez, E.R. (2005) Glucocorticoid receptor and heat shock factor 1: novel mechanism of reciprocal regulation. Vitam. Horm. 71:239-262.
• Yang, Z., Wolf, I.M., Chen, H., Periyasamy, S., Chen, Z., Yong, W., Shi, S., Zhao, W., Xu, J., Srivastava, A., Sanchez, E.R., and Shou, W. (2006) FKBP52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform. Mol Endocrinol.  (11):2682-2694.
• Yong, W., Yang, Z., Periyasamy, S., Chen, H., Yucel, S., Li, W., Lin, L.Y., Wolf, I.M., Cohn, M.J., Baskin, L.S., Sanchez, E.R., and Shou, W.  (2007)  Essential role for Co-chaperone Fkbp52 but not Fkbp51 in androgen receptor-mediated signaling and physiology.  J. Biol. Chem. 282(7):5026-5036.
• Periyasamy, S., Warrier, M., Tillekeratne, M.P., Shou, W., and Sanchez, E.R.  (2007)  The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms.  Endocrinology. 148(10):4716-4726.
• Yong, W., Bao, S., Chen, H., Li, D., Sanchez, E.R., and Shou, W.  (2007) Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest.  J Biol Chem. May 18;282(20):14690-14694.
• Hinds, T.D., Jr. and Sanchez, E.R.  (2007)  Protein phosphatase 5.  Int J Biochem Cell Biol. 2007 Aug 30.
• Heitzer, M.D., Wolf, I.M., Sanchez, E.R., Witchel, S.F., and DeFranco, D.B.  (2007) Glucocorticoid receptor physiology.  Rev Endocr Metab Disord. Dec;8(4):321-330.
• Banerjee, A., Periyasamy, S., Wolf, I.M., Hinds, T.D., Jr, Yong, W., Shou, W. and Sanchez, E.  (2008) Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins.  Biochemistry Sep 30; 47(39):10471-80. Epub 2008 Sep 5
• Wolf, I.M., Periyasamy, S., Hinds, T. Jr., Yong, W., Shou, W., and Sanchez, E.R.  (2008) Targeted ablation reveals a novel role of FKBP52 in gene-specific regulation of glucocorticoid receptor transcriptional activity.  J. Steroid Biochem Mol Biol Nov 27 [Epub ahead of print]