Adrenarche is the peri-pubertal event that occurs when the human adrenal begins to make large amounts of 19-carbon androgen precursors, especially dehydroepiandrosterone (DHEA). Children normally begin adrenarche at about age 8-9, before the onset of puberty. Clinical studies show that early, exaggerated adrenarche may be an early sign of the polycystic ovary syndrome (PCOS), which affects 3-5% of women of reproductive age. PCOS women have increased secretion of C-19 steroids 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 C-19 steroid produced in both tissues. P450c17 catalyzes both 17a-hydroxylase and 17,20 lyase activities. When expressed in the zona fasciculata, P450c17 catalyzes 17(t-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 ratio of hydroxylase to lyase activities is not constant, but is regulated at the post-translational level, at least in part by serine/threonine phosphorylation. Phosphorylation of P450c17 preferentially increases lyase activity. Dephosphorylation of P450c17 by protein phosphatase PP2A inhibits lyase activity without affecting 17a-hydroxylase activity. Thus, I hypothesize that the phosphorylation by protein kinase and dephosphorylation by protein phosphatase of P450c17 are two physiologically important pathways in regulating human adrenal androgen production. I propose to test this hypothesis by pursuing four specific aims.
Aim 1 : Identify the specific phosphorylated serine and threonine residues on P450c17 critical for 17,20 lyase activity.
Aim 2 : Determine whether phosphorylation of serine residues influences association with P450 oxidoreductase and/or cytochrome b5.
Aim 3 : Identify the kinase(s) responsible for P450c17 phosphorylation.
Aim 4 : Define the regulatory subunit(s) of phosphatase PP2A responsible for dephosphorylation of P450c17. Fulfillment of these four aims will 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.
| Dong, Qing; Cheng, Zhiqiang; Chang, Wenhan et al. (2010) Naturally-occurring mutation in the calcium-sensing receptor reveals the significance of extracellular domain loop III region for class C G-protein-coupled receptor function. J Clin Endocrinol Metab 95:E245-52 |
| Tee, Meng Kian; Dong, Qing; Miller, Walter L (2008) Pathways leading to phosphorylation of p450c17 and to the posttranslational regulation of androgen biosynthesis. Endocrinology 149:2667-77 |
