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.[1]References
- Developmental action of estrogen receptor-alpha feminizes the growth hormone-Stat5b pathway and expression of Cyp2a4 and Cyp2d9 genes in mouse liver. Sueyoshi, T., Yokomori, N., Korach, K.S., Negishi, M. Mol. Pharmacol. (1999) [Pubmed]
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