Adrenarche is the peri-pubertal event when the human adrenal begins to make large amounts of 19-carbon steroids, especially dehydroepiandrosterone (DHEA). Children normally begin adrenarche at about age 8-9 before the onset of puberty. Clinical studies show that early, exaggerated adrenarche maybe an early sign of the polycystic ovary syndrome (PCOS), which affects 3-5 percent of women of reproductive age. PCOS women have increased secretion of C-19 androgens from both the adrenals and ovaries. The conversion of 17OH pregnenolone to DHEA by the 17,20 lyase activity of cytochrome p450c17 determines the amount of androgen produced in both tissues. P450c17 catalyzes both 17alpha-hydroxylase and 17,20 lyase activities. Each activity requires the donation of a pair of electrons from p450 oxidoreductase (OR). The mechanisms of the tissue-specific expression of P450c17 in the adrenal and gonad are unknown. When expressed in the zona fasciculata, P450c17 catalyzes 17alpha- hydroxylase but very little 17,20 lyase activity to produce cortisol. When it is expressed in the adrenal zona reticularis and in the gonad, it has high 17,20 lyase activity and catalyzes the formation of DHEA, the precursor of androgens and estrogens. At least two factors regulate the 17,20 lyase activity of P450c17 at a post-translational level: the presence of cytochrome b5, which allosterically fosters the interaction of P450cl7 with OR, and serine phosphorylation of P450c17, which increases 17,20 lyase activity by unknown mechanisms. We propose to elucidate the key transcriptional and post-translational mechanisms of regulation of P450c17 by pursuing four specific aims.
Aim 1 : Identify the factors required for tissue-specific basal transcription of the human p450c17 gene.
Aims 2 : Identify the kinase(s) responsible for P450c17 phosphorylation.
Aim 3 : Determine whether the degree of phosphorylation of P450c17 is regulated by dephosphorylation (phosphatases).
Aim 4 : Determine how P450c17 phosphorylation influences 17,20 lyase activity. Fulfillment of these four aims will greatly expand our understanding of the mechanisms by which androgen production is regulated in both health and disease and should provide novel insights into the mechanisms by which the adrenals and gonads of women with PCOS overproduce androgens.
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