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首页> 外文期刊>Biochemistry >Phosphorylation of STAT3 Serine-727 by Cyclin-Dependent Kinase 1 Is Critical for Nocodazole-Induced Mitotic Arrest
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Phosphorylation of STAT3 Serine-727 by Cyclin-Dependent Kinase 1 Is Critical for Nocodazole-Induced Mitotic Arrest

机译：周期蛋白依赖性激酶1磷酸化STAT3丝氨酸727对诺考达唑诱导的有丝分裂逮捕至关重要。

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Signal transducer and activator of transcription 3 (STAT3) mediates cellular responses to diverse cytokines and growth factors by modulating the expression of specific target genes.While phosphorylation of STAT3 at Tyr-705 has been demonstrated to be a prerequisite for STAT3 dimerization,nuclear translocation,and activation of gene transcription,the role of Ser-727 in regulation of STAT3 activity is controversial.Kinetworks KPSS-1.1 phospho-site screening of nocodazole-treated HeLa cells revealed that STAT3 Ser-727 phosphorylation was enhanced during mitosis,and this correlated with a reduction of Tyr-705 phosphorylation.Overexpression of STAT3 mutants in which these phosphorylation sites were separately abolished revealed that phosphorylation at these sites appeared to be mutually antagonistic.The nocodazole-induced STAT3 Ser-727 phosphorylation was reduced by selective inhibition of CDK1 phosphotransferase activity,and CDK1 could directly phosphorylate GST-STAT3 Ser-727 in vitro and co-immunoprecipitate with STAT3 in vivo.Blocking Ser-727 phosphorylation enhanced STAT3 DNA-binding activity toward its target gene promoters,implying a negative effect of Ser-727 phosphorylation on its transcriptional activity.Interference of Ser-727 phosphorylation resulted in an exit from mitotic arrest induced by nocodazole treatment and a cell cycle arrest at the G1 phase,as indicated by the accumulation of 2N cell population and enhanced expression of Gl cell cycle regulators including p21~(CIP1/WAF1),p27~(Kip1),and cyclin E.Taken together,our observations point to a novel role of STAT3 Ser-727 phosphorylation in control of the onset and maintenance of the M phase during the cell cycle through downregulation of CDK inhibitors.
机译：信号转导和转录激活因子3（STAT3）通过调节特定靶基因的表达来介导细胞对多种细胞因子和生长因子的反应。虽然已证明STAT3在Tyr-705上的磷酸化是STAT3二聚化，核易位，以及基因转录的激活，Ser-727在调节STAT3活性中的作用尚存争议。Kinetworks对Nocodazole处理的HeLa细胞进行KPSS-1.1磷酸位点筛选显示，STAT3 Ser-727磷酸化在有丝分裂过程中增强，这与这些磷酸化位点被分别消除的STAT3突变体的过表达表明，这些位点的磷酸化似乎是相互拮抗的。通过选择性抑制CDK1磷酸转移酶的活性，减少了诺考达唑诱导的STAT3 Ser-727磷酸化。 ，而CDK1可以在体外直接磷酸化GST-STAT3 Ser-727和在体内与STAT3共同免疫沉淀。阻断Ser-727磷酸化增强了STAT3 DNA对靶基因启动子的结合活性，这暗示了Ser-727磷酸化对其转录活性的负面影响.Ser-727磷酸化的干扰导致其退出诺考达唑处理诱导的有丝分裂阻滞和G1期的细胞周期阻滞，如2N细胞群体的积累和p21〜（CIP1 / WAF1），p27〜（Kip1）和细胞周期蛋白的G1细胞周期调节子表达增强所表明的。 E.综合起来，我们的观察结果表明，STAT3 Ser-727磷酸化通过下调CDK抑制剂，在控制细胞周期期间M期的发作和维持中具有新的作用。

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