赖氨酸 685 在转录因子未磷酸化 STAT3 介导的基因表达中起关键作用。
Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3.
机构信息
Departments of Molecular Genetics and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
Departments of Molecular Cardiology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
出版信息
J Biol Chem. 2014 Oct 31;289(44):30763-30771. doi: 10.1074/jbc.M114.603894. Epub 2014 Sep 12.
STAT3 is a pleiotropic transcription factor that is activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. STAT3 without Tyr-705 phosphorylation (U-STAT3) is also a potent transcription factor, and its concentration in cells increases greatly in response to STAT3 activation because the STAT3 gene can be driven by phosphorylated STAT3 dimers. We have now searched for post-translational modifications of U-STAT3 that might have a critical role in its function. An analysis by mass spectroscopy indicated that U-STAT3 is acetylated on Lys-685, and the integrity of Lys-685 is required for the expression of most U-STAT3-dependent genes. In contrast, we found only a very minor role for Lys-685 in gene expression induced in response to tyrosine-phosphorylated STAT3. U-STAT3 plays an important role in angiotensin II-induced gene expression and in the consequent development of cardiac hypertrophy and dysfunction. Mutation of Lys-685 inhibits this function of STAT3, providing new information on the role of U-STAT3 in augmenting the development of heart failure.
STAT3 是一种多效转录因子，可被多种细胞因子和生长因子响应性的酪氨酸 705 磷酸化激活。无 Tyr-705 磷酸化的 STAT3（U-STAT3）也是一种有效的转录因子，其在细胞中的浓度会因 STAT3 的激活而大大增加，因为 STAT3 基因可以被磷酸化的 STAT3 二聚体驱动。我们现在正在寻找 U-STAT3 的翻译后修饰，这些修饰可能在其功能中具有关键作用。质谱分析表明，U-STAT3 在 Lys-685 上发生乙酰化，并且 Lys-685 的完整性是表达大多数 U-STAT3 依赖性基因所必需的。相比之下，我们发现 Lys-685 在响应酪氨酸磷酸化的 STAT3 诱导的基因表达中仅发挥很小的作用。U-STAT3 在血管紧张素 II 诱导的基因表达及其随后的心脏肥大和功能障碍的发展中起重要作用。Lys-685 突变抑制了 STAT3 的这一功能，为 U-STAT3 在增强心力衰竭发展中的作用提供了新信息。
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