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Vol. 56, Issue 3, 473-477, September 1999
Feminizes the
Growth Hormone-Stat5b Pathway and Expression of Cyp2a4 and
Cyp2d9 Genes in Mouse Liver
Pharmacogenetics (T.S., N.Y., M.N.) and Receptor Biology (K.S.K.)
Sections, Laboratory of Reproductive and Developmental Toxicology,
National Institute of Environmental Health Sciences, National
Institutes of Health, Research Triangle Park, North Carolina
We have studied the roles of estrogen receptor-
(ER) and the Stat5b form of STAT (signal transducers and
activators of transcription) in sex-specific expression of
Cyp2a4 (steroid 15-hydroxylase) and
Cyp2d9 (steroid 16-hydroxylase) genes using
ER-deficient mice. ER deficiency resulted in the repression of
the female-specific Cyp2a4 and expression of the
male-specific Cyp2d9 genes, respectively in females. In
ER-deficient males, the Cyp2d9 gene continued to be
expressed. Nuclear localization of Stat5b occurs in both sexes of
ER-deficient mice, although it is normally observed in only
wild-type males. Nuclear localization of Stat5b correlates with the
repression of Cyp2a4 and expression of
Cyp2d9, respectively. Because Stat5b was not detectable
in liver nuclear extracts prepared from hypophysectomized
ER-deficient females, the regulation by ER appeared to be
mediated through a pituitary hormone (i.e., growth hormone). Thus,
ER appears to play a key role in the mechanism that inhibits nuclear
localization of Stat5b in female mice, leading to feminization of a
ER-GH-Stat5b pathway and Cyp expression. Defaulting
to this ER-dependent mechanism results in localization of Stat5b to
nuclei, which masculinizes the expression of Cyp genes
in male mice.
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