Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation
Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation
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DOI：
10.1073/pnas.0900121106
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发表时间：
2010-01-05
影响因子：
11.1
通讯作者：
Larsson, Lars-Gunnar
中科院分区：
文献类型：
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作者：
Hydbring, Per;Bahram, Fuad;Larsson, Lars-Gunnar
MYC和RAS癌基因在癌症中经常被激活，并且一起足以转化啮齿动物细胞。这种合作的基础仍然不清楚。我们发现，尽管Ras干扰Myc诱导的细胞凋亡，但Myc抑制Ras诱导的衰老，共同消除了肿瘤发生的两个主要障碍。细胞衰老的抑制需要Myc在Ser-62处通过细胞周期蛋白E/细胞周期蛋白依赖性激酶（Cdk）2磷酸化。Cdk 2在启动子处与Myc相互作用，在启动子处影响Myc依赖的基因调控，包括Bmi-1、p16、p21和hTERT，这些基因编码已知控制衰老的蛋白质。Myc对衰老的抑制被Cdk抑制剂p27 Kip 1消除，这是由抗增殖信号如IFN-γ或Cdk 2的药理学抑制剂诱导的，但不是由其他Cdk的抑制剂诱导的。相比之下，磷酸模拟Myc-S62 D突变体对这些操作具有抗性。细胞周期蛋白E/Cdk 2的抑制逆转了Myc/细胞周期蛋白E/Cdk 2施加的衰老相关基因表达模式。这表明Cdk 2作为Myc抗衰老功能的转录辅因子和激活剂的作用，并提供了对Myc-p27 Kip 1拮抗作用的机制见解。最后，我们的研究结果强调了Cdk 2活性的药理学抑制是癌症治疗的潜在治疗原则，特别是对于具有活化的Myc或Ras的肿瘤。
The MYC and RAS oncogenes are frequently activated in cancer and, together, are sufficient to transform rodent cells. The basis for this cooperativity remains unclear. We found that although Ras interfered with Myc-induced apoptosis, Myc repressed Ras-induced senescence, together abrogating two main barriers of tumorigenesis. Inhibition of cellular senescence required phosphorylation of Myc at Ser-62 by cyclin E/cyclin-dependent kinase (Cdk) 2. Cdk2 interacted with Myc at promoters, where it affected Myc-dependent regulation of genes, including Bmi-1, p16, p21, and hTERT, which encode proteins known to control senescence. Repression of senescence by Myc was abrogated by the Cdk inhibitor p27Kip1, which is induced by antiproliferative signals like IFN-gamma or by pharmacological inhibitors of Cdk2 but not by inhibitors of other Cdks. In contrast, a phospho-mimicking Myc-S62D mutant was resistant to these manipulations. Inhibition of cyclin E/Cdk2 reversed the senescence-associated gene expression pattern imposed by Myc/cyclin E/Cdk2. This indicates a role of Cdk2 as a transcriptional cofactor and activator of the antisenescence function of Myc and provides mechanistic insight into the Myc-p27Kip1 antagonism. Finally, our findings highlight that pharmacological inhibition of Cdk2 activity is a potential therapeutical principle for cancer therapy, in particular for tumors with activated Myc or Ras.