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J. Biol. Chem., Vol. 278, Issue 5, 2837-2844, January 31, 2003
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From the Cytochrome P450c17 catalyzes
17
Protein Phosphatase 2A and Phosphoprotein SET Regulate Androgen
Production by P450c17*
,¶
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
-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 17-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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