Mechanisms of Mineralcorticoid Receptor Function

University Of California San Francisco, San Francisco CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) are hormone activated transcription factors that impact on the function of virtually every mammalian tissue. This proposal focuses on the mechanistic basis of MR and GR regulation of gene expression, particularly in systems with importance to blood pressure regulation and stress responses. The following hypotheses motivate our future goals: 1) Non-receptor cellular factors are important determinants of the robust and transient induction of a subset of MR- and GR-regulated genes, in particular, SGK1; 2) Synergy control is an important determinant of MR and GR activities, particularly in regulating phenylethanolamine N-methyltransferase (PNMT), the glucocorticoid-regulated enzyme that catalyzes the conversion of norepinephrine to epinephrine. Synergy control is determined by interactions between the DBD and N-terminal domains and requires receptor modification by non-receptor factors, which include the recently discovered ubiquitin-like protein, SUMO1 Based on these considerations, we will: 1) Determine the mechanism of rapid induction of SGK1 gene transcription by MR and GR. We will: (a) identify and characterize hormone response elements involved in the induction of SGK1 gene transcription by MR and GR; (b) determine the role of chromatin modification and transcriptional synergy in the induction of SGK1 gene transcription. 2) Determine the mechanism of down-regulation ("deinduction") of SGK1 gene expression. We will: (a) Characterize the time course of SGK1 mRNA regulation in rat kidney; (b) determine if new protein synthesis is required for the deinduction of SGK1 gene expression in CCD cells; (C) assess the role of chromatin and non-chromatin factors in SGK1 deinduction; (d) examine the role of mRNA stability in SGK1 deinduction. 3) Determine the mechanistic basis of synergy control and its role in MR and GR activity and specificity. We will: (a) functionally characterize the 5' regulatory region of PNMT; (b) identify cellular factors required for controlling MR and GR synergistic activity; (c) examine the determinants and consequences of SUMO1 modification of GR and MR. Together, these studies will extend our understanding of the gene regulatory mechanisms that underlie blood pressure regulation and responses to stress and potentially lead to new avenues for the prevention and treatment of disease.