Developmental action of estrogen receptor-alpha feminizes the growth hormone-Stat5b pathway and expression of Cyp2a4 and Cyp2d9 genes in mouse liver.
We have studied the roles of estrogen receptor-alpha (ERalpha) and the Stat5b form of STAT (signal transducers and activators of transcription) in sex-specific expression of Cyp2a4 (steroid 15alpha-hydroxylase) and Cyp2d9 (steroid 16alpha-hydroxylase) genes using ERalpha-deficient mice. ERalpha deficiency resulted in the repression of the female-specific Cyp2a4 and expression of the male-specific Cyp2d9 genes, respectively in females. In ERalpha-deficient males, the Cyp2d9 gene continued to be expressed. Nuclear localization of Stat5b occurs in both sexes of ERalpha-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 ERalpha-deficient females, the regulation by ERalpha appeared to be mediated through a pituitary hormone (i.e., growth hormone). Thus, ERalpha appears to play a key role in the mechanism that inhibits nuclear localization of Stat5b in female mice, leading to feminization of a ERalpha-GH-Stat5b pathway and Cyp expression. Defaulting to this ERalpha-dependent mechanism results in localization of Stat5b to nuclei, which masculinizes the expression of Cyp genes in male mice.
Sueyoshi
T
T
Pharmacogenetics, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Yokomori
N
N
Korach
K S
KS
Negishi
M
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002467:Cell Nucleus / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D007016:Hypophysectomy; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008894:Milk Proteins; D011960:Receptors, Estrogen / Q000172:deficiency / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D008894:Milk Proteins; D011960:Receptors, Estrogen; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C504575:CYP2D9 protein, mouse; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C050356:steroid 15-alpha-hydroxylase