Udy G B, Towers R P, Snell R G, Wilkins R J, Park S H, Ram P A, Waxman D J, Davey H W
Dairy Science Group, AgResearch, Ruakura, Private Bag 3123, Hamilton, New Zealand.
Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7239-44. doi: 10.1073/pnas.94.14.7239.
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 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.
信号转导子与转录激活子STAT5b参与了多种细胞因子和生长因子的信号转导途径，包括生长激素（GH）。脉冲式而非持续性的GH暴露通过酪氨酸磷酸化激活肝脏中的STAT5b，导致其二聚化、核转位以及STAT的转录激活，这被认为在调节由脉冲式血浆GH诱导的肝脏基因表达的性别二态性中起关键作用。我们使用小鼠基因敲除模型评估了STAT5b对于GH脉冲生理效应的重要性。STAT5b基因破坏导致与垂体GH分泌的性别二态模式相关的多种性别分化反应的重大丧失。在STAT5b - / - 雄性小鼠中，雄性特征的身体生长速率和雄性特异性肝脏基因表达降至野生型雌性水平，而雌性占主导的肝脏基因产物增加到野生型雄性和雌性水平之间的中间水平。尽管这些反应与在GH缺乏的矮小（Little）小鼠中观察到的反应相似，但STAT5b - / - 小鼠并非GH缺乏，这表明它们可能对GH脉冲有抗性。实际上，STAT5b - / - 小鼠中出现的侏儒症、血浆GH升高、血浆胰岛素样生长因子I降低以及肥胖的发展都是拉伦氏（Laron）型侏儒症的特征，这是一种通常与GH受体缺陷相关的人类GH抵抗疾病。STAT5b对于维持身体生长速率和肝脏基因表达的性别二态性的需求表明，STAT5b可能是介导肝脏以及可能其他靶组织中GH脉冲的性别二态效应的主要（如果不是唯一的）STAT蛋白。因此，STAT5b具有独特的生理功能，令人惊讶的是，高度同源的STAT5a无法替代这些功能。
