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
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DOI：
10.1073/pnas.94.14.7239
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发表时间：
1997-07-08
影响因子：
11.1
通讯作者：
Davey, HW
中科院分区：
文献类型：
--
作者：
Udy, GB;Towers, RP;Davey, HW
信号转导子和转录激活子STAT 5 b参与了许多细胞因子和生长因子（包括生长激素（GH））的信号转导途径。脉冲但不连续的GH暴露通过酪氨酸磷酸化激活肝脏STAT 5 b，导致STAT的二聚化、核转位和转录激活，这被认为在调节脉冲血浆GH诱导的肝脏基因表达的性二型性中起关键作用。我们使用小鼠基因敲除模型评估了STAT 5 b对GH脉冲的生理效应的重要性。STAT 5 b基因破坏导致与垂体GH分泌的性二态性模式相关的多种性分化反应的主要丧失。在STAT 5 b（-/-）雄性中，雄性特征性身体生长率和雄性特异性肝脏基因表达降低至野生型雌性水平，而雌性主导的肝脏基因产物增加至野生型雄性和雌性水平之间的中间水平。虽然这些反应与GH缺陷型小鼠中观察到的反应相似，但STAT 5 b（-/-）小鼠不是GH缺陷型小鼠，这表明它们可能对GH脉冲具有抗性。事实上，侏儒症，血浆GH升高，血浆胰岛素样低。生长因子I和在STAT 5 b（-/-）小鼠中观察到的肥胖发展都是Laron型侏儒症的特征，Laron型侏儒症是一种通常与GH受体缺陷相关的人GH抗性疾病。STAT 5 b维持身体生长速率和肝脏基因表达的性二态性的要求表明，STAT 5 b可能是主要的，如果不是唯一的，STAT蛋白介导的性二态性效应的GH脉冲在肝脏和其他靶组织。因此，STAT 5 b具有独特的生理功能，令人惊讶的是，高度同源的STAT 5a无法取代。
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 fed to a major loss of multiple, sexually differentiated responses associated with the sexually dimorphic pattern of pituitary GH secretion. Male-characteristic 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 pulse-resistant. 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.