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J. Biol. Chem., Vol. 280, Issue 5, 3259-3268, February 4, 2005

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Role of Hepatocyte Nuclear Factors in Transcriptional Regulation of Male-specific CYP2A2^*

Christopher A. Wiwi and David J. Waxman

From the Division of Cell and Molecular Biology, Department of Biology Boston University, Boston, Massachusetts 02215

Cytochrome P450 2A2 (CYP2A2) is an adult male-specific rat liver steroid hydroxylase whose sex-dependent expression is regulated at the transcriptional level by sexually dimorphic pituitary growth hormone (GH) secretory patterns. In contrast to CYP2C11 and other male-specific, plasma GH pulse-inducible liver genes, CYP2A2 is highly expressed in hypophysectomized rat liver, despite the absence of GH stimulation. CYP2A2 promoter fragments 0.9–6.2 kb long exhibited unusually high basal promoter activity when transfected into the liver cell line HepG2. A further 2.5-fold increase in activity was obtained by cotransfection of hepatocyte nuclear factor (HNF) 3 or HNF4. CYP2A2 promoter activity was inhibited 85% by transfection of HNF3 or HNF6, both of which are more highly expressed in female than male liver and can strongly trans-activate the female-specific CYP2C12 promoter. The male GH pulse-activated transcription factor STAT5b had no effect on CYP2A2 promoter activity, either alone or in combination with HNF3 and HNF4, consistent with the GH pulse-independence of CYP2A2 expression. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4 toward two other male-specific liver target genes, Cyp2d9 and CYP8B1. Furthermore, STAT5b in combination with the HNF4 coactivator peroxisome proliferator-activated receptor coactivator-1 strongly enhanced the transcriptional activity of HNF4 toward CYP8B1 but not toward CYP2A2. These findings support the hypothesis that sex-dependent HNFs contribute to the sexually dimorphic expression of CYP2A2 and other liver CYPs and highlight the ability of STAT5b to act in concert with HNF4 to regulate select male-specific liver CYP genes.

Received for publication, August 13, 2004 , and in revised form, November 5, 2004.

^* This work was supported by National Institutes of Health Grant DK33765 (to D. J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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 Biology, Boston University, 5 Cummington St., Boston, MA 02215. Fax: 617-353-7404; E-mail: djw{at}bu.edu.

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