Hormonal regulation of the thyrotropin beta-subunit gene by phosphorylation of the pituitary-specific transcription factor Pit-1.
Hormonal regulation of the thyrotropin beta-subunit gene by phosphorylation of the pituitary-specific transcription factor Pit-1.
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通过垂体特异性转录因子 Pit-1 的磷酸化对促甲状腺素 β 亚基基因进行激素调节。
DOI：
10.1073/pnas.89.13.5942
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发表时间：
1992
影响因子：
11.1
通讯作者：
Wondisford,FE
中科院分区：
文献类型：
--
作者：
Steinfelder,HJ;Radovick,S;Wondisford,FE
垂体特异性转录因子Pit-1是垂体前叶催乳素和生长激素基因转录的细胞特异性激活因子。Pit-1也被证明介导促甲状腺素释放激素（TRH）和cAMP刺激催乳素和促甲状腺素β亚基（TSH β）基因。Pit-1介导这些刺激作用的分子机制仍不清楚。TSH β基因中至少有三个Pit-1结合元件介导对TRH和cAMP的反应。本研究旨在验证磷酸化是Pit-1与TSH β基因相互作用的重要调节剂这一假设。与催乳素和生长激素基因中的高亲和力Pit-1结合位点不同，TSH β元件与非磷酸化Pit-1的结合不如与磷酸化Pit-1的结合好，并且是基因表达的弱激活剂。通过蛋白激酶A或C的磷酸化增强Pit-1与TSH β元件的结合3至8倍。相反，磷酸化通常减少Pit-1与催乳素和生长激素基因内的元件的结合。TSH β基因元件中Pit-1结合的共有序列内的变异[TSH β基因中的A（A/T）（A/T）AATNCAT与催乳素和生长激素基因中的A（A/T）（A/T）TATNCAT]可以解释这些差异。这些元件可能通过与非磷酸化Pit-1结合不太好而限制TSH β基因的基础激活，同时通过增强磷酸化Pit-1的结合而赋予激素刺激。
The pituitary-specific transcription factor Pit-1 is a cell-specific activator of prolactin and growth hormone gene transcription in the anterior pituitary. Pit-1 has also been shown to mediate both thyrotropin-releasing hormone (TRH) and cAMP stimulation of the prolactin and thyrotropin beta-subunit (TSH beta) genes. The molecular mechanism by which Pit-1 mediates these stimulatory effects remains unclear. At least three Pit-1-binding elements within the TSH beta gene mediate responsiveness to TRH and cAMP. The present studies were designed to test the hypothesis that phosphorylation is an important modulator of Pit-1 interaction with the TSH beta gene. TSH beta elements bind less well to nonphosphorylated Pit-1 than to phosphorylated Pit-1 and are weak activators of gene expression, unlike high-affinity Pit-1 binding sites in the prolactin and growth hormone genes. Phosphorylation by protein kinase A or C enhances Pit-1 binding to TSH beta elements 3- to 8-fold. Conversely, phosphorylation generally reduces binding of Pit-1 to elements within the prolactin and growth hormone genes. A variation within the consensus sequence for Pit-1 binding in TSH beta gene elements [A(A/T)(A/T)AATNCAT in the TSH beta gene versus A(A/T)(A/T)TATNCAT in the prolactin and growth hormone genes] could explain these differences. These elements may limit basal activation of the TSH beta gene by binding less well to nonphosphorylated Pit-1 while conferring hormonal stimulation through enhanced binding of phosphorylated Pit-1.