STAT 5 and NF-Y are involved in expression and growth hormone-mediated sexually dimorphic regulation of cytochrome P450 3A10/lithocholic acid 6beta-hydroxylase

Subramanian, Asha; Wang, Jianming; Gil, Gregorio

doi:10.1093/nar/26.9.2173

Cited by 39 publications

(21 citation statements)

References 37 publications

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“…This elevation of normally female-dominant liver enzyme levels suggests that STAT5b may negatively regulate some GH-regulated liver-expressed genes in addition to its demonstrated positive effects on the transcriptional activation of certain male GH pulse-stimulated genes (22). 2 This model is in accord with other studies based on an analysis of CYP enzyme patterns in GH-deficient lit/lit mice, where it is shown that the low expression in male mouse liver of several female-specific, GH-regulated CYP enzymes is at least in part due to the suppressive effects of male GH pulses (2,6).…”

Section: Figmentioning

confidence: 99%

“…STAT5 proteins thus have the potential to contribute to multiple signaling pathways associated with cell growth and differentiation. The proposed mediation by STAT5 of GH pulse-regulated, sexually dimorphic liver gene expression (12) is supported by the finding of a functional STAT5 response element in the promoter region of several male-specific, GH pulse-regulated genes (22). 2 In addition, targeted disruption of Stat5b leads to a major loss of multiple, sexually differentiated responses associated with pulsatile GH secretion (23), demonstrating that this GH pulse-activatable transcription factor (12) is essential for maintaining sexually dimorphic body growth rates and liver gene expression.…”

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confidence: 91%

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Distinctive Roles of STAT5a and STAT5b in Sexual Dimorphism of Hepatic P450 Gene Expression

Park¹,

Liu²,

Hennighausen³

et al. 1999

Journal of Biological Chemistry

142

104

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Stat5b gene disruption leads to an apparent growth hormone (GH) pulse insensitivity associated with loss of male-characteristic body growth rates and male-specific liver gene expression (Udy, G. B., Towers, R. P., Snell, R. G., Wilkins, R. J., Park, S. H., Ram, P. A., Waxman, D. J., and Davey, H. W. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 7239 -7244). In the present study, disruption of the mouse Stat5a gene, whose coding sequence is ϳ90% identical to the Stat5b gene, resulted in no loss of expression in male mice of several sex-dependent, GHregulated liver cytochrome P450 (CYP) enzymes. By contrast, the loss of STAT5b feminized the livers of males by decreasing expression of male-specific CYPs (CYP2D9 and testosterone 16␣-hydroxylase) while increasing to female levels several female-predominant liver CYPs (CYP3A, CYP2B, and testosterone 6␤-hydroxylase). Since STAT5a is thus nonessential for these male GH responses, STAT5b homodimers, but not STAT5a-STAT5b heterodimers, probably mediate the sexually dimorphic effects of male GH pulses on liver CYP expression. In female mice, however, disruption of either Stat5a or Stat5b led to striking decreases in several liver CYP-catalyzed testosterone hydroxylase activities. Stat5a or Stat5b gene disruption also led to the loss of a female-specific, GH-regulated hepatic CYP2B enzyme. STAT5a, which is much less abundant in liver than STAT5b, and STAT5b are therefore both required for constitutive expression in female but not male mouse liver of certain GH-regulated CYP steroid hydroxylases, suggesting that STAT5 protein heterodimerization is an important determinant of the sex-dependent and genespecific effects that GH has on the liver.The cytochrome P450s (CYPs) 1 are a superfamily of heme proteins that hydroxylate steroid hormones and other endogenous chemicals as well as numerous drugs and environmental carcinogens. CYPs are highly expressed in liver, where they are subject to complex hormonal regulation and sex-dependent expression. Prototypic examples of sex-specific liver CYPs in the rat model are the male-specific CYP2C11 (testosterone 16␣-and 2␣-hydroxylase) and the female-specific CYP2C12 (steroid sulfate 15␤-hydroxylase) (1). Marked sex-dependent differences in hepatic CYP profiles are also seen in the mouse, where CYP2D9 (a testosterone 16␣-hydroxylase) and CYP2A4 (a testosterone 15␣-hydroxylase) are expressed in males and females, respectively, in certain strains (2, 3). Sexually dimorphic expression of a mouse CYP2B testosterone 16␣-hydroxylase has also been described (4 -6). The expression of these sexually dimorphic liver steroid hydroxylase CYPs is primarily determined by the sexual dimorphism of plasma growth hormone (GH) profiles (2, 7-9). Intermittent plasma GH pulses, a characteristic of adult male rats, induce expression of male-specific CYP proteins and their associated steroid hydroxylase activities, while the near continuous presence of GH in the plasma of adult female rats induces expression of female-specific and female-dominant liver CYP protein...

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Section: Figmentioning

confidence: 99%

mentioning

confidence: 91%

Distinctive Roles of STAT5a and STAT5b in Sexual Dimorphism of Hepatic P450 Gene Expression

Park¹,

Liu²,

Hennighausen³

et al. 1999

Journal of Biological Chemistry

142

104

View full text Add to dashboard Cite

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“…Rsl could interact with STAT5b directly on the promoters of GH pulse-responsive, male-specific liver genes, which contain functional, albeit weak, STAT5b binding sites (Subramanian et al 1998;Park and Waxman 2001). Alternatively, Rsl may block the action of one or more of the liver-enriched transcription factors (hepatocyte-enriched nuclear factors, HNFs) whose expression or activity is regulated by GH and STAT5b (Lahuna et al 2000;Rastegar et al 2000;Park and Waxman 2001;Piwien-Pilipuk et al 2002) and may contribute to the sex-dependence of liver gene expression.…”

Section: Genes and Development 2609mentioning

confidence: 99%

Sexual dimorphism of hepatic gene expression: novel biological role of KRAB zinc finger repressors revealed: Figure 1.

Waxman¹,

Celenza²

2003

Genes Dev.

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“…4 and 5). Presumably, STAT5b acts in a positive manner to stimulate expression of CYP2D9 and other male-expressed liver CYPs by trans-activating STAT5 response elements found in the 5Ј-flanking DNA of this group of genes (21). 2 The mechanism responsible for the apparent negative regulation by STAT5b of certain female-expressed liver CYPs (e.g.…”

Section: Figmentioning

confidence: 99%

“…Further confirmation came from the finding that certain GH pulse-regulated, male-specific liver P450 genes contain STAT5 response elements (21), from the recent demonstration that STAT5b nuclear localization correlates with the gender-specific expression of P450 genes in wild-type and estrogen receptor-␣-deficient mice (22), and from our analysis of STAT5b-deficient mice, which displayed loss of malespecific pubertal body growth and male-specific liver gene expression (23). However, it is unclear from these studies whether GH target tissues such as liver become unresponsive to pulsatile GH as a direct consequence of the loss of STAT5b, or whether an alteration in the pattern of pituitary GH secretion in these animals leads to the observed phenotypes.…”

mentioning

confidence: 99%

STAT5b-deficient Mice Are Growth Hormone Pulse-resistant

Davey¹,

Park²,

Grattan³

et al. 1999

Journal of Biological Chemistry

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The signal transducer and transcriptional activator STAT5b is required to maintain the adult male pattern of liver gene expression and whole body pubertal growth rates, as demonstrated by the loss of these growth hormone (GH) pulse-dependent responses in mice with a targeted disruption of the STAT5b gene. The present study investigates whether these phenotypes of STAT5b-deficient mice result from impaired intracellular GH signaling associated with a loss of GH pulse responsiveness, as contrasted with a feminization of the pituitary GH secretory profile leading to the observed feminization of body growth and liver gene expression. Pulsatile GH replacement in hypophysectomized mice stimulated body weight gain in wild-type but not in STAT5b-deficient mice. Expression of the male-specific liver P450 enzyme CYP2D9, which is reduced to female levels in hypophysectomized male mice, was restored to male levels by GH pulse replacement in wild-type but not in STAT5b-deficient mice. Similarly, a female-specific liver CYP2B P450 enzyme that was up-regulated to female levels following hypophysectomy of males was suppressed to normal basal male levels by GH pulses only in wild-type hypophysectomized mice. Finally, urinary excretion of the male-specific, GH pulse-induced major urinary protein was restored to normal male levels following pulsatile GH treatment only in the case of wild-type hypophysectomized mice. STAT5b-deficient mice are thus GH pulse-resistant, supporting the proposed role of STAT5b as a key intracellular mediator of the stimulatory effects of plasma GH pulses on the male pattern of liver gene expression. Growth hormone (GH)1 has diverse effects on metabolism and growth that can result from the direct effects of GH on gene expression, or may be indirectly mediated by factors such as insulin-like growth factor I (1). In addition, the temporal patterns of pituitary GH secretion differ in males and females in many species, resulting in the expression of some genes predominantly in males and other genes predominantly in females (2-4). In male rats, plasma GH pulses are separated by periods of Ͼ2 h during which there is negligible GH detectable in blood. In contrast, the female plasma GH pattern is characterized by a more continuous presence of GH or, in some species such as mice, by more frequent pulses of GH (3,5).GH binds to cell surface receptors that dimerize upon hormone binding and subsequently activate the receptor-associated tyrosine kinase JAK2. JAK2 in turn phosphorylates itself and the GH receptor on multiple tyrosine residues. STAT proteins are then recruited to the GH receptor/JAK2 complex and are phosphorylated on tyrosine and subsequently on serine. STAT proteins activated in this manner form homo-or heterodimers and translocate to the nucleus where they bind to target sites in GH-responsive genes (6, 7). STAT5 proteins in the liver are intermittently, and repeatedly, activated in response to GH pulses (8, 9). GH also activates liver STAT1 and STAT3, but the activation of these STATs is largely ind...

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STAT 5 and NF-Y are involved in expression and growth hormone-mediated sexually dimorphic regulation of cytochrome P450 3A10/lithocholic acid 6beta-hydroxylase

Cited by 39 publications

References 37 publications

Distinctive Roles of STAT5a and STAT5b in Sexual Dimorphism of Hepatic P450 Gene Expression

Distinctive Roles of STAT5a and STAT5b in Sexual Dimorphism of Hepatic P450 Gene Expression

Sexual dimorphism of hepatic gene expression: novel biological role of KRAB zinc finger repressors revealed: Figure 1.

STAT5b-deficient Mice Are Growth Hormone Pulse-resistant

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