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Originally published In Press as doi:10.1074/jbc.M209527200 on November 19, 2002

J. Biol. Chem., Vol. 278, Issue 5, 2837-2844, January 31, 2003
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Protein Phosphatase 2A and Phosphoprotein SET Regulate Androgen Production by P450c17*

Amit V. PandeyDagger , Synthia H. Mellon§, and Walter L. MillerDagger ||

From the Dagger  Department of Pediatrics and § Department of Obstetrics, Gynecology, and Reproductive Sciences, the  Metabolic Research Unit and the Center for Reproductive Sciences, University of California, San Francisco, California 94143-0978

Cytochrome P450c17 catalyzes 17alpha -hydroxylation needed for cortisol synthesis and 17,20 lyase activity needed to produce sex steroids. Serine phosphorylation of P450c17 specifically increases 17,20 lyase activity, but the physiological factors regulating this effect remain unknown. Treating human adrenal NCI-H295A cells with the phosphatase inhibitors okadaic acid, fostriecin, and cantharidin increased 17,20 lyase activity, suggesting involvement of protein phosphatase 2A (PP2A) or 4 (PP4). PP2A but not PP4 inhibited 17,20 lyase activity in microsomes from cultured cells, but neither affected 17alpha -hydroxylation. Inhibition of 17,20 lyase activity by PP2A was concentration-dependent, could be inhibited by okadaic acid, and was restored by endogenous protein kinases. PP2A but not PP4 coimmunoprecipitated with P450c17, and suppression of PP2A by small interfering RNA increased 17,20 lyase activity. Phosphoprotein SET found in adrenals inhibited PP2A, but not PP4, and fostered 17,20 lyase activity. The identification of PP2A and SET as post-translational regulators of androgen biosynthesis suggests potential additional mechanisms contributing to adrenarche and hyperandrogenic disorders such as polycystic ovary syndrome.

* This work was supported by National Institutes of Health Grants HD34449 (to W. L. M.), HD41958 (to W. L. M.), and HD27970 (to S. H. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Dept. of Pediatrics, Bldg. MR4, Rm. 209, University of California, San Francisco, CA 94143-0978. Tel.: 415-476-2598; Fax: 415-476-6286; E-mail: wlmlab@itsa.ucsf.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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