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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Role of cdk2 in the sequential phosphorylation/activation of C/EBPβ during adipocyte differentiation
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Role of cdk2 in the sequential phosphorylation/activation of C/EBPβ during adipocyte differentiation

机译：cdk2在脂肪细胞分化过程中C /EBPβ顺序磷酸化/激活中的作用

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摘要

Upon induction of differentiation, growth-arrested (G_1 phase) 3T3-L1 preadipocytes express CCAAT/enhancer binding protein-β (C/EBPβ), initiating a transcriptional cascade. C/EBPβ immediately undergoes a priming phosphorylation (on Thr_(188)) by MAPK/ERK. However, the acquisition of DNA binding and transactivation capacity of C/EBPβ is delayed until further phosphorylation (on Ser_(184) or Thr_(179)) by GSK3β occurs. Phosphorylation by glycogen synthase kinase-3β (GSK3β) induces S phase entry and thereby mitotic clonal expansion (MCE), a requirement for terminal differentiation. Because MAPK activity is down-regulated before S phase is completed, we sought to identify the kinase that maintains C/EBPβ in the primed phosphorylated state throughout S phase and MCE. We show here that cdk2/cyclinA, whose expression is activated at the onset of S phase, functions in this capacity. Ex vivo and in vitro experiments show that cdk2/cyclinA catalyzes this delayed priming phosphorylation. Mass spectrometric analysis revealed that cdk2/cyclinA phosphorylates C/EBPβ on Thr_(188) and is required for phosphorylation (on Ser_(184) or Thr_(179)) of C/EBPβ by GSK3β and maintenance of DNA binding activity. Suppression of cdk2 activity by RNA interference or pharmacologic inhibitor disrupts subsequent events in the differentiation program. Thus, MAPK and cdk2/cyclinA act sequentially to maintain Thr_(188) of C/EBPβ in the primed phosphorylated state during MCE and thereby progression of terminal differentiation.
机译：诱导分化后，生长停滞（G_1期）的3T3-L1前脂肪细胞表达CCAAT /增强子结合蛋白-β（C /EBPβ），从而启动转录级联反应。 C /EBPβ立即通过MAPK / ERK进行引发磷酸化（在Thr_（188）上）。但是，直到C /EBPβ的DNA结合和反式激活能力的获取被延迟，直到GSK3β进一步磷酸化（在Ser_（184）或Thr_（179）上）。糖原合酶激酶3β（GSK3β）进行的磷酸化诱导S期进入，从而诱导有丝分裂克隆扩增（MCE），这是终末分化的必要条件。由于MAPK活性在S期完成之前被下调，因此我们试图确定在整个S期和MCE中维持C /EBPβ处于引发的磷酸化状态的激酶。我们在这里显示cdk2 / cyclinA，其表达在S期开始时被激活，以这种能力发挥作用。体外和体外实验表明，cdk2 / cyclinA催化这种延迟的启动磷酸化作用。质谱分析显示，cdk2 / cyclinA使Thr_（188）上的C /EBPβ磷酸化，是GSK3β对C /EBPβ的磷酸化作用（在Ser_（184）或Thr_（179）上）和维持DNA结合活性所必需的。 RNA干扰或药理抑制剂抑制cdk2活性会破坏分化程序中的后续事件。因此，MAPK和cdk2 / cyclinA顺序发挥作用，以在MCE期间将C /EBPβ的Thr_（188）维持在引发的磷酸化状态，从而促进终末分化。

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