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首页> 外文期刊>Molecular and Cellular Biology >DNA Damage-Induced G1 Arrest in Hematopoietic Cells Is Overridden following Phosphatidylinositol 3-Kinase-Dependent Activation of Cyclin-Dependent Kinase 2
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DNA Damage-Induced G1 Arrest in Hematopoietic Cells Is Overridden following Phosphatidylinositol 3-Kinase-Dependent Activation of Cyclin-Dependent Kinase 2

机译：磷酸化肌醇3-激酶依赖细胞周期蛋白依赖性激酶2的激活后，在造血细胞中DNA损伤诱导的G1逮捕被覆盖。

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Exposure of hematopoietic cells to DNA-damaging agents induces p53-independent cell cycle arrest at a G1 checkpoint. Previously, we have shown that this growth arrest can be overridden by cytokine growth factors, such as erythropoietin or interleukin-3, through activation of a phosphatidylinositol 3-kinase (PI 3-kinase)/Akt-dependent signaling pathway. Here, we show that γ-irradiated murine myeloid 32D cells arrest in G1 with active cyclin D–cyclin-dependent kinase 4 (Cdk4) but with inactive cyclin E-Cdk2 kinases. The arrest was associated with elevated levels of the Cdk inhibitors p21Cip1 and p27Kip1, yet neither was associated with Cdk2. Instead, irradiation-induced inhibition of cyclin E-Cdk2 correlated with absence of the activating threonine-160 phosphorylation on Cdk2. Cytokine treatment of irradiated cells induced Cdk2 phosphorylation and activation, and cells entered into S phase despite sustained high-level expression of p21 and p27. Notably, the PI 3-kinase inhibitor, LY294002, completely blocked cytokine-induced Cdk2 activation and cell growth in irradiated 32D cells but not in nonirradiated cells. Together, these findings demonstrate a novel mechanism underlying the DNA damage-induced G1 arrest of hematopoietic cells, that is, inhibition of Cdk2 phosphorylation and activation. These observations link PI 3-kinase signaling pathways with the regulation of Cdk2 activity.
机译：造血细胞暴露于DNA损伤剂会在G 1 检查点诱导p53依赖性细胞周期停滞。以前，我们已经表明，通过激活磷脂酰肌醇3激酶（PI 3激酶）/ Akt依赖性信号传导途径，这种生长停滞可以被诸如促红细胞生成素或白细胞介素3等细胞因子生长因子所取代。在这里，我们显示，γ射线照射的鼠髓系32D细胞在细胞周期蛋白D–细胞周期蛋白依赖性激酶4（Cdk4）激活而细胞周期蛋白E-Cdk2激酶失活的情况下在G 1 中停滞。逮捕与Cdk抑制剂p21 Cip1 和p27 Kip1 升高有关，但均与Cdk2无关。相反，辐射诱导的细胞周期蛋白E-Cdk2抑制与Cdk2上不存在苏氨酸160活化磷酸化有关。细胞因子对受辐照细胞的处理诱导Cdk2磷酸化和激活，尽管p21和p27持续高水平表达，但细胞仍进入S期。值得注意的是，PI 3激酶抑制剂LY294002完全阻断了受细胞因子诱导的Cdk2活化和受辐照的32D细胞中的细胞生长，但未阻断未受辐照的细胞中的细胞生长。总之，这些发现证明了DNA损伤诱导的造血细胞G 1 停滞的新机制，即抑制Cdk2磷酸化和激活。这些观察结果将PI 3-激酶信号传导途径与Cdk2活性的调节联系起来。

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