Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulin-like growth factor binding protein-1 gene transcription: A mechanism for repression of gene expression by growth hormone
Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulin-like growth factor binding protein-1 gene transcription: A mechanism for repression of gene expression by growth hormone
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DOI：
10.1210/me.2006-0543
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发表时间：
2007-06-01
影响因子：
--
通讯作者：
Rotwein, Peter
中科院分区：
文献类型：
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作者：
Ono, Mitsuru;Chia, Dennis J.;Rotwein, Peter
生长激素通过依赖于基因表达调控的机制在控制大多数脊椎动物的体细胞生长、组织再生和中间代谢中发挥核心作用。最近的研究使用转录谱已经确定了大的基因，其表达是由GH诱导的队列。其他结果表明，信号转导和转录激活因子（Stat）5 b，一种由GH受体相关蛋白激酶Jak 2激活的潜在转录因子，是GH刺激基因激活导致体细胞生长的关键因子。相比之下，很少有人知道通过GH启动的信号通路减少基因表达的步骤。在这里，我们表明，Stat 5 b通过损害FoxO 1转录因子对IGF结合蛋白-1启动子的作用，在GH调节的IGF结合蛋白-1基因转录抑制中起着至关重要的作用。在肝脏中使用转录谱的其他观察表明，Stat 5 b可能是GH启动的基因抑制的一般介质。我们的研究结果提供了一个模型，了解生长激素如何通过相同的转录因子同时刺激和抑制不同基因组的表达，可能解释生长激素的作用如何导致整个生物体的综合生物反应。
GH plays a central role in controlling somatic growth, tissue regeneration, and intermediary metabolism in most vertebrate species through mechanisms dependent on the regulation of gene expression. Recent studies using transcript profiling have identified large cohorts of genes whose expression is induced by GH. Other results have demonstrated that signal transducer and activator of transcription (Stat) 5b, a latent transcription factor activated by the GH receptor-associated protein kinase, Jak2, is a key agent in the GH-stimulated gene activation that leads to somatic growth. By contrast, little is known about the steps through which GH-initiated signaling pathways reduce gene expression. Here we show that Stat5b plays a critical role in the GH-regulated inhibition of IGF binding protein-1 gene transcription by impairing the actions of the FoxO1 transcription factor on the IGF binding protein-1 promoter. Additional observations using transcript profiling in the liver indicate that Stat5b may be a general mediator of GH-initiated gene repression. Our results provide a model for understanding how GH may simultaneously stimulate and inhibit the expression of different cohorts of genes via the same transcription factor, potentially explaining how GH action leads to integrated biological responses in the whole organism.