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. ? 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. ? 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. ? 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. ? ?
| Finco, Isabella; Lerario, Antonio M; Hammer, Gary D (2018) Sonic Hedgehog and WNT Signaling Promote Adrenal Gland Regeneration in Male Mice. Endocrinology 159:579-596 |
| Penny, Morgan K; Finco, Isabella; Hammer, Gary D (2017) Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia. Mol Cell Endocrinol 445:42-54 |
| Lerario, Antonio Marcondes; Finco, Isabella; LaPensee, Christopher et al. (2017) Molecular Mechanisms of Stem/Progenitor Cell Maintenance in the Adrenal Cortex. Front Endocrinol (Lausanne) 8:52 |
| Xing, Yewei; Morohashi, Ken-Ichirou; Ingraham, Holly A et al. (2017) Timing of adrenal regression controlled by synergistic interaction between Sf1 SUMOylation and Dax1. Development 144:3798-3807 |
| Bornstein, Stefan R; Allolio, Bruno; Arlt, Wiebke et al. (2016) Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 101:364-89 |
| Basham, Kaitlin J; Hung, Holly A; Lerario, Antonio M et al. (2016) Mouse models of adrenocortical tumors. Mol Cell Endocrinol 421:82-97 |
| Nanba, Kazutaka; Omata, Kei; Tomlins, Scott A et al. (2016) Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations. Eur J Endocrinol 175:K1-6 |
| Nanba, Kazutaka; Chen, Andrew X; Omata, Kei et al. (2016) Molecular Heterogeneity in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab 101:999-1007 |
| Lee, Jiwon; Yang, Dong Joo; Lee, Syann et al. (2016) Nutritional conditions regulate transcriptional activity of SF-1 by controlling sumoylation and ubiquitination. Sci Rep 6:19143 |
| Finco, Isabella; LaPensee, Christopher R; Krill, Kenneth T et al. (2015) Hedgehog signaling and steroidogenesis. Annu Rev Physiol 77:105-29 |
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