Phosphorylation of CtBP1 by cAMP-dependent protein kinase modulates induction of CYP17 by stimulating partnering of CtBP1 and 2
Phosphorylation of CtBP1 by cAMP-dependent protein kinase modulates induction of CYP17 by stimulating partnering of CtBP1 and 2
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DOI：
10.1074/jbc.m708432200
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发表时间：
2008-03-14
影响因子：
4.8
通讯作者：
Sewer, Marion B.
中科院分区：
文献类型：
--
作者：
Dammer, Eric B.;Sewer, Marion B.
在人肾上腺皮质中，肽类激素促肾上腺皮质激素 (ACTH) 通过激活 cAMP/cAMP 依赖性蛋白激酶 (PKA) 途径来指导皮质醇和肾上腺雄激素的生物合成。羧基末端结合蛋白 1 (CtBP1) 是一种辅阻遏物，通过响应 ACTH 信号传导定期与类固醇生成因子 1 相互作用来调节 CYP17 基因的转录。鉴于 CtBP1 功能受 NADH 结合调节，我们假设 ACTH 刺激的细胞吡啶核苷酸浓度变化调节 CtBP1 抑制 CYP17 转录的能力。此外，我们假设 PKA 引起 CtBP1 磷酸化状态的变化，从而控制蛋白质与类固醇生成因子 1 和共激活剂 GCN5（一般控制非去阻遏 5）结合的能力并抑制 CYP17 基因表达。我们发现 ACTH 会改变吡啶核苷酸氧化还原状态，并识别 CtBP1 中 PKA 和 PAK6 靶向的氨基酸残基。 ACTH/cAMP 信号传导和 NADH/NAD(+) 比率都会刺激两种 CtBP 蛋白的核胞质振荡。我们提供的证据表明，PKA 1) 诱导肾上腺皮质的代谢变化，2) 磷酸化 CtBP 蛋白，特别是 T144 处的 CtBP1，导致 CtBP 蛋白配对和 ACTH 依赖性 CYP17 转录。
In the human adrenal cortex, the peptide hormone adrenocorticotropin (ACTH) directs cortisol and adrenal androgen biosynthesis by activating a cAMP/cAMP-dependent protein kinase (PKA) pathway. Carboxyl-terminal binding protein 1 (CtBP1) is a corepressor that regulates transcription of the CYP17 gene by periodically interacting with steroidogenic factor-1 in response to ACTH signaling. Given that CtBP1 function is regulated by NADH binding, we hypothesized that ACTH-stimulated changes in cellular pyridine nucleotide concentrations modulate the ability of CtBP1 to repress CYP17 transcription. Further, we postulated that PKA evokes changes in the phosphorylation status of CtBP1 that control the ability of the protein to bind to steroidogenic factor-1 and the coactivator GCN5 (general control nonderepressed 5) and repress CYP17 gene expression. We show that ACTH alters pyridine nucleotide redox state and identify amino acid residues in CtBP1 that are targeted by PKA and PAK6. Both ACTH/cAMP signaling and NADH/NAD(+) ratio stimulate nuclear-cytoplasmic oscillation of both CtBP proteins. We provide evidence that PKA 1) induces metabolic changes in the adrenal cortex and 2) phosphorylates CtBP proteins, particularly CtBP1 at T144, resulting in CtBP protein partnering and ACTH-dependent CYP17 transcription.