[25] Expression of genes within mouse IIA and IID subfamilies: Simultaneous measurement of homologous P450 mRNAs

Negishi, Masahiko; Burkhart, Barbara A.; Aida, Kaoru

doi:10.1016/0076-6879(91)06096-l

Cited by 8 publications

(10 citation statements)

References 7 publications

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“…4B). The individual animal variation seen in these samples may be due to the random genetic contribution from the 129 ϫ BALB͞c outcrossed background, because these two strains are known to differ in their patterns of expression of these proteins (43). Similarly, STAT5b gene disruption in males increased expression of the femaledominant liver CYP3A proteins and their associated microsomal testosterone 6␤-hydroxylase activity to near-female levels (Fig.…”

Section: Stat5bmentioning

confidence: 99%

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression

Udy

Towers

Snell

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

910

697

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The signal transducer and activator of transcription, STAT5b, has been implicated in signal transduction pathways for a number of cytokines and growth factors, including growth hormone (GH). Pulsatile but not continuous GH exposure activates liver STAT5b by tyrosine phosphorylation, leading to dimerization, nuclear translocation, and transcriptional activation of the STAT, which is proposed to play a key role in regulating the sexual dimorphism of liver gene expression induced by pulsatile plasma GH. We have evaluated the importance of STAT5b for the physiological effects of GH pulses using a mouse gene knockout model. STAT5b gene disruption led to a major loss of multiple, sexually differentiated responses associated with the sexually dimorphic pattern of pituitar y GH secretion. Malecharacteristic body growth rates and male-specific liver gene expression were decreased to wild-type female levels in STAT5b ؊͞؊ males, while female-predominant liver gene products were increased to a level intermediate between wild-type male and female levels. Although these responses are similar to those observed in GH-deficient Little mice, STAT5b ؊͞؊ mice are not GH-deficient, suggesting that they may be GH pulseresistant. Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like growth factor I, and development of obesity seen in STAT5b ؊͞؊ mice are all characteristics of Laron-type dwarfism, a human GH-resistance disease generally associated with a defective GH receptor. The requirement of STAT5b to maintain sexual dimorphism of body growth rates and liver gene expression suggests that STAT5b may be the major, if not the sole, STAT protein that mediates the sexually dimorphic effects of GH pulses in liver and perhaps other target tissues. STAT5b thus has unique physiological functions for which, surprisingly, the highly homologous STAT5a is unable to substitute.

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Section: Stat5bmentioning

confidence: 99%

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression

Udy

Towers

Snell

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

910

697

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“…Moreover, unlike in the rat, there are major strain differences in Cyp gene expression patterns in the mouse (4,34,35) (Tables I and III). For example, whereas testosterone 15␣-hydroxylase activity has been associated with the femalepredominant CYP2A4, and testosterone 16␣-hydroxylase activity represents the male-specific CYP2D9 in some mouse strains, these P450 enzyme activities are also associated with other CYP gene products and consequently lose their sex-dependence in other mouse strains (Table III) (4,31).…”

Section: Stat5amentioning

confidence: 99%

“…To achieve this objective, we first examined the patterns of CYP enzyme expression in male and female Stat5a Ϫ/Ϫ and Stat5b Ϫ/Ϫ mice, using the diagnostic CYP substrate testosterone (32). Liver CYP enzyme patterns are known to differ significantly between individual strains of mice (2,34,35). We observed several differences in the sex-dependence of liver microsomal testosterone hydroxylation in the two mouse strains used in this study, 129J ϫ Black Swiss for Stat5a Ϫ/Ϫ and 129J inbred for Stat5b Ϫ/Ϫ .…”

Section: Expression Of Sex-dependent Cyps In Stat5amentioning

confidence: 99%

“…Our previous study of Stat5b Ϫ/Ϫ mice (23) was carried out using 129J ϫ BALB/c outbred mice. Since there are significant strain differences in the patterns of CYP enzyme expression in mouse liver (4,34,35), we generated Stat5b Ϫ/Ϫ mice in the 129J inbred strain in order to eliminate random genetic contributions from the 129J ϫ BALB/c outcrossed background to individual animal variation. Examination of the Stat5b Ϫ/Ϫ 129J congenic mice revealed effects of STAT5b disruption on liver STAT protein expression similar to those seen earlier in outbred mice; STAT1 levels were increased, while the expression of STAT3 and STAT5a was unchanged (data not shown).…”

Section: Stat5amentioning

confidence: 99%

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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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“…Some hepatic P450s are sex specific in their expressions, which leads to sex-specific metabolism of such endogenous substances as steroids and of exogenous chemicals including procarcinogens. For example, mouse steroid 16␣-hydroxylase P450 16␣ (Cyp 2d-9) is expressed only in male livers, whereas mouse steroid 15␣-hydroxylase P450 15␣ (Cyp 2a-4) is expressed only in female livers (1,23,24,26,42,45). Similarly, rat steroid 16␣-hydroxylase (CYP 2C11) and steroid sulfate 15␤-hydroxylase (CYP 2C12) are male-and female-specific P450s, respectively (34,35,40).…”

mentioning

confidence: 99%

A Nuclear Factor (NF2d9) That Binds to the Male-Specific P450 (Cyp 2d-9) Gene in Mouse Liver

Sueyoshi

Kobayashi

Nishio

et al. 1995

Molecular and Cellular Biology

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Expression of the Cyp 2d-9 (steroid 16␣-hydroxylase) gene in mouse liver is male specific in such Mus musculus domesticus strains as FVB/N, whereas the corresponding P450 genes in the wild mouse species Mus spretus are not sex specific in their expression. These parental differences in the gene expressions were independently inherited in F 1 offspring from crosses of FVB/N and M. spretus. A 5 flanking sequence ( ؊110 CTC CTCCCTATTCCGGGCC ؊92) was defined as a regulatory element (named SDI-A1) for the domestic Cyp 2d-9 promoter. The nucleotide which corresponds to T at position ؊99 within SDI-A1 was found to be substituted with C in the wild mouse P450 genes. The placing of C at position ؊99 abolished the transcriptional activity of SDI-A1 in HepG2 cells as well as the binding of SDI-A1 to a nuclear factor. This factor (designated NF2d9) was purified from mouse nuclear extracts, and its cDNA was cloned. The purified NF2d9 bound to SDI-A1 but not to the mutated SDI-A1 with C at position ؊99. The deduced amino acid sequence revealed that NF2d9 is 72 and 94% identical to mouse CP2 and human LBP-1a, respectively. NF2d9 thus belongs to the CP2 family and is the mouse homolog of human LBP-1a, which modulates human immunodeficiency virus type 1 transcription. Anti-NF2d9, which was raised against the bacterially expressed protein, supershifted the SDI-A1 complex with the liver nuclear extract. Both the bacterially expressed and in vitro-translated NF2d9 inhibited SDI-A1 complex formation, although they did not bind to SDI-A1 directly. The results, therefore, indicate that the domestic Cyp 2d-9 gene can be regulated through a specific association of NF2d9 with SDI-A1.The P450 gene exhibits extremely divergent expressions which are regulated differently by various hormones and xenobiotics. Understanding the regulatory mechanisms is a major interest in P450 research (28). Some hepatic P450s are sex specific in their expressions, which leads to sex-specific metabolism of such endogenous substances as steroids and of exogenous chemicals including procarcinogens. For example, mouse steroid 16␣-hydroxylase P450 16␣ (Cyp 2d-9) is expressed only in male livers, whereas mouse steroid 15␣-hydroxylase P450 15␣ (Cyp 2a-4) is expressed only in female livers (1,23,24,26,42,45). Similarly, rat steroid 16␣-hydroxylase (CYP 2C11) and steroid sulfate 15␤-hydroxylase (CYP 2C12) are male-and female-specific P450s, respectively (34,35,40). It is known that these sex-specific P450 genes are transcriptionally regulated by the sexually differentiated secretion patterns of growth hormone (18, 21-23, 26, 35, 46). However, neither a cis-acting regulatory element nor a trans-acting factor for the sex-specific transcription has yet been identified.Despite the high identity of its nucleotide sequence with that of male-specific Cyp 2d-9, the other gene subfamily member, Cyp 2d-10, is constitutively expressed in both male and female mice (41). By taking advantage of this high sequence identity and the diverse expressions of the two P450 genes, Yoshioka ...

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[25] Expression of genes within mouse IIA and IID subfamilies: Simultaneous measurement of homologous P450 mRNAs

Cited by 8 publications

References 7 publications

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression

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

A Nuclear Factor (NF2d9) That Binds to the Male-Specific P450 (Cyp 2d-9) Gene in Mouse Liver

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