Distinctive roles of STAT5a and STAT5b in sexual dimorphism of hepatic P450 gene expression -: Impact of Stat5a gene disruption
Distinctive roles of STAT5a and STAT5b in sexual dimorphism of hepatic P450 gene expression -: Impact of Stat5a gene disruption
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DOI：
10.1074/jbc.274.11.7421
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发表时间：
1999-03-12
影响因子：
4.8
通讯作者：
Waxman, DJ
中科院分区：
文献类型：
--
作者：
Park, SH;Liu, XW;Waxman, DJ
STAT5B基因突变导致明显的生长激素(GH)脉冲不敏感，与男性特有的身体生长速度和男性特有的肝脏基因表达的丧失有关(Udy，G，B，，Towers，R.P，，Snell，R.G，，Wilkins，R，J，，Park，S，H，，Ram，P，A.，Waxman，D，J，和Davey，H，W，(1997)Proc.娜塔莉。阿卡德。SCI。美国94,7239-7244)。在本研究中，小鼠Stat5a基因的编码序列与Stat5b基因相似，其编码序列与Stat5b基因90%相似，破坏该基因并未导致雄性小鼠几种性别相关的、生长激素调节的肝脏细胞色素P450(CYP)酶的表达丢失。相比之下，STAT5b的缺失通过减少男性特有的细胞色素P450(CYP2D9和睾酮16α-羟基酶)的表达，而增加女性主导的几种肝脏细胞色素P450(细胞色素P3A、细胞色素P450 B和睾酮6β-羟基酶)的表达，使男性的肝脏女性化。由于STAT5a对这些男性GH反应不是必需的，STAT5b同源二聚体，而不是Stat5a-STAT5b异源二聚体，可能介导了男性GH脉冲对肝脏CYP表达的性二态效应。然而，在雌性小鼠中，Stat5a或Stat5b的干扰导致肝脏CYP催化的几种睾酮羟基酶活性显著降低。Stat5a或Stat5b基因的中断也会导致女性特有的、生长激素调节的肝脏细胞色素P450 2 B酶的丢失。因此，STAT5a和STAT5b都是GH调节的某些CYP类固醇羟基酶在雌性小鼠肝脏而不是雄性小鼠肝脏构成表达所必需的，这表明STAT5蛋白异二聚化是GH对肝脏产生性别依赖性和基因特异性效应的重要决定因素。
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 similar to 90% identical to the Stat5b gene, resulted in no loss of expression in male mice of several sex-dependent, GH-regulated 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 alpha-hydroxylase) while increasing to female levels several female-predominant liver CYPs (CYP3A, CYP2B, and testosterone 6 beta-droxylase). 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 gene-specific effects that GH has on the liver.