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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation
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Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation

机译：Myc抑制共转化中Ras诱导的衰老需要Cdk2磷酸化

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摘要

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 antiprolifer-ative signals like IFN-γ 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.
机译：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。这种合作的基础尚不清楚。我们发现，尽管Ras干扰了Myc诱导的细胞凋亡，但Myc抑制了Ras诱导的衰老，共同消除了肿瘤发生的两个主要障碍。抑制细胞衰老需要细胞周期蛋白E /细胞周期蛋白依赖性激酶（Cdk）使Ser-62处的Myc磷酸化。Cdk2在启动子上与Myc相互作用，从而影响Myc依赖性基因的调控，包括Bmi-1，p16，p21和hTERT，它们编码已知可控制衰老的蛋白质。 Cdk抑制剂p27Kip1废除了Myc对衰老的抑制作用，该抑制剂是由抗增殖信号（如IFN-γ）或Cdk2的药理抑制剂诱导的，而不是由其他Cdks的抑制剂诱导的。相反，模仿磷的Myc-S62D突变体对这些操作有抵抗力。细胞周期蛋白E / Cdk2的抑制逆转了Myc /细胞周期蛋白E / Cdk2施加的衰老相关基因表达模式。这表明Cdk2作为Myc的抗衰老功能的转录辅因子和激活剂的作用，并提供了对Myc-p27Kip1拮抗作用的机理见解。最后，我们的发现突出了Cdk2活性的药理抑制作用是癌症治疗的潜在治疗原理，特别是对于Myc或Ras活化的肿瘤。

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    Per Hydbring; Fuad Bahram; Yingtao Su; Susanna Tronnersjoe; Kari Hoegstrand; Natalie von der Lehr; Hamid Reza Sharif/; Richard Lilischkis; Nadine Hein; Siqin Wu; Joerg Vervoorts; Marie Henriksson; Alf Grandien; Bernhard Luescher; Lars-Gunnar Larsson;

  • 作者单位

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden;

    Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden;

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52057 Aachen, Germany;

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;

    Department of Medicine, Karolinska University Hospital-Huddinge, 141 86 Stockholm, Sweden;

    Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden;

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;

    Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52057 Aachen, Germany;

    Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52057 Aachen, Germany;

    Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden;

    Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52057 Aachen, Germany;

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;

    Department of Medicine, Karolinska University Hospital-Huddinge, 141 86 Stockholm, Sweden;

    Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52057 Aachen, Germany;

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    oncogenes; transcription; cell cycle; p27Kip1; cyclin E;

    机译：癌基因转录细胞周期;p27Kip1;细胞周期蛋白E;

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