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Submitted on August 10, 2005
Accepted on October 11, 2005
*
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215
* To whom correspondence should be addressed. E-mail: djw{at}bu.edu.
Targeted disruption of STAT5b leads to decreased expression in male mouse liver of a male-predominant cytochrome (Cyp) 2d protein, while female-predominant Cyp2b proteins are increased. Presently, we characterize the effects of STAT5b deficiency on 15 specific, individual Cyp RNAs and other sexually dimorphic liver gene products. All 7 male-specific RNAs investigated were decreased to normal female levels in STAT5b-deficient male liver, while 5 of 8 female-specific RNAs, designated class-I female genes, were increased in expression up to 
200-fold. STAT5b deficiency had a much more modest effect on the expression of these genes in females. Hypophysectomy and GH replacement studies demonstrated positive GH pulse regulation of all 7 male RNAs, and negative GH pulse regulation of class-I, but not class-II, female RNAs, in wild-type but not in STAT5b-deficient male mice. A majority of the sex-specific genes responded in parallel to the loss of STAT5b and to the loss of hepatocyte nuclear factor (HNF)4
, indicating that both transcription factors are essential, and may co-regulate sexually dimorphic liver gene expression. Continuous GH treatment of intact male mice, which overrides the endogenous male, pulsatile plasma GH pattern, down-regulated all 7 male RNAs and induced expression of the 5 class-I female RNAs within 4-7d; however, induction of class-II female RNAs was delayed until day 7-14. Given the slow responses of all 15 genes to changes in plasma GH status, GH regulation of sex-specific Cyp expression is proposed to be indirect, mediated by STAT5b- and HNF4-dependent factors that may include repressors of female-specific Cyps and other targets of GH action.
•
cytochrome P450 •
liver sexual dimorphism •
growth hormone
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