The long term objective of this project is a thorough understanding of how steroid hormone synthesis is regulated in a developmental and tissue-specific fashion, and how dysregulation may result in reproductive disorders such as polycystic ovarian syndrome (PCOS). The genes for steroidogenic enzymes are transcriptionally regulated at several levels: developmentally, tissue specifically, and hormonally. This regulation shares common features but also differs among the various genes for the steroidogenic enzymes and among various mammals. We will focus on the gene encoding P450c17 (17alpha hydroxylase/17,2 lyase) as it is the key branch point in steroidogenesis, it has been implicated in the etiology of PCOS, and it may be involved in early development of nervous and reproductive systems. Its expression in the human adrenal is required for the synthesis of 17 hydroxy C21 steroids (e.g. cortisol) and for synthesis of C19 sex steroids in the gonads and brain. In the nervous system, expression of P450c17 also results in DHEA synthesis, a potent neuromodulators. We have been using the rodent as our model system for studying the transcriptional regulation of this gene, and have identified cis-acting DNA elements and several novel trans-acting nuclear factors. One of these transcription factors, SET, had been identified from a chromosomal translocation in a patient with acute undifferentiated leukemia, but its role as a transcription factor way unknown. We shall now determine the mechanism of SET action by identifying its DNA binding, transactivation, and potential dimerization domains, and identifying co-factors that may interact with SET to participate in its transactivating functions. AS SET is abundantly expressed and regulates P450c17 expression in the developing gonad and nervous system, we will determine if these co-factors are tissue- specifically expressed, and/or if they modify other known functions of SET. Our studies localizing cis-active elements in the rat P450c17 gene have identified a region bound by a factor that we call StF-IT-2, that interacts with the orphan nuclear receptor SF-1 in a novel way, to regulate P450c17 transcription. We will characterize that interaction, and purify, characterize and clone the cDNA for StF-IT-2. Successful completion of these studies will give us a better understanding of how the gonadal and nervous systems initiate steroidogenesis, the mechanism of action of a new class of transcription factor, novel mechanisms by which SF-1 regulates gene expression, and will identify another transcription factor that may participate in a unique aspect of P450c17 expression.
| Shi, Yimin; Schonemann, Marcus D; Mellon, Synthia H (2009) Regulation of P450c17 expression in the early embryo depends on GATA factors. Endocrinology 150:946-56 |
| Mellon, Synthia H; Bair, Susanna R; Depoix, Christophe et al. (2007) Translin coactivates steroidogenic factor-1-stimulated transcription. Mol Endocrinol 21:89-105 |
| Brake, Paul B; Bair, Susanna R; Mellon, Synthia H (2005) DNA sequence-dependent regulation of SF-1-mediated transcription. DNA Cell Biol 24:148-60 |
| Hammer, Fabian; Compagnone, Nathalie A; Vigne, Jean-Louis et al. (2004) Transcriptional regulation of P450scc gene expression in the embryonic rodent nervous system. Endocrinology 145:901-12 |
| Mellon, Synthia; Gong, Wenhui; Griffin, Lisa D (2004) Niemann pick type C disease as a model for defects in neurosteroidogenesis. Endocr Res 30:727-35 |
| Bair, Susanna R; Mellon, Synthia H (2004) Deletion of the mouse P450c17 gene causes early embryonic lethality. Mol Cell Biol 24:5383-90 |
| Pandey, Amit V; Mellon, Synthia H; Miller, Walter L (2003) Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. J Biol Chem 278:2837-44 |
| Mellon, Synthia H; Griffin, Lisa D (2002) Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab 13:35-43 |
| Chanoine, J P; Compagnone, N A; Wong, A C et al. (2001) Modulation of steroidogenesis by selenium in a novel adrenal cell line developed using targeted tumorigenesis. Biofactors 14:229-38 |
| Griffin, L D; Conrad, S C; Mellon, S H (2001) Current perspectives on the role of neurosteroids in PMS and depression. Int Rev Neurobiol 46:479-92 |
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