Mechanisms of Adrenal Differentiation

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The long-range objective of our laboratory is to understand the biochemical mechanisms by which cell-type specific transcription factors direct the differentiation of adrenocortical cells within the adrenal gland. [unreadable] Our strategy for this proposal is to focus on transcriptional regulation mediated by the orphan nuclear receptor, steroidogenic factor-1 (SF-1), a transcription factor that is required for the differentiation of the adrenal cortex. Targeted disruption of the gene encoding SF-1 (Ftzf1, Nr5a1) leads to mouse embryos that lack adrenal glands while point mutations that affect the ability of SF-1 to associate with nuclear receptor coregulators, bind DNA and ultimately activate target genes, result in adrenal insufficiency in humans. [unreadable] Based on our preliminary data, we hypothesize that SF-1 mediated transcriptional activation is specifically regulated by adrenocorticotropin hormone (ACTH) and involves intramolecular modifications and intermolecular protein interactions that serve to modulate transcriptional activation to ultimately control adrenal cell differentiation. [unreadable] Our specific aims are therefore directed towards a systematic analysis of the modification of the SF-1 transcriptional complex by ACTH. We propose to determine the major nuclear phosphoprotein targets of ACTH together with a characterization of the signaling cascades responsible for phosphorylation of components of the complex (specific aim 1), how these modifications regulate the organization of the SF-1 transcription complex (specific aim 2) and the contribution of specific phosphoprotein components of the complex to ACTH-dependent target gene activation in the adrenocortical cell (specific aim 3). We believe that the studies proposed here will provide the framework for understanding the molecular events that dictate adrenocortical cell differentiation. [unreadable] [unreadable]