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p16INK4A Participates in a G1 Arrest Checkpoint in Response to DNA Damage

机译：p16INK4A参与对DNA损伤的G1逮捕检查站

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Members of the INK4 protein family specifically inhibit cyclin-dependent kinase 4 (cdk4) and cdk6-mediated phosphorylation of the retinoblastoma susceptibility gene product (Rb). p16INK4A, a prototypic INK4 protein, has been identified as a tumor suppressor in many human cancers. Inactivation of p16INK4A in tumors expressing wild-type Rb is thought to be required in order for many malignant cell types to enter S phase efficiently or to escape senescence. Here, we demonstrate another mechanism of tumor suppression by implicating p16INK4A in a G1 arrest checkpoint in response to DNA damage. Calu-1 non-small cell lung cancer cells, which retain Rb and lack p53, do not arrest in G1 following DNA damage. However, engineered expression of p16INK4A at levels compatible with cell proliferation restores a G1 arrest checkpoint in response to treatment with γ-irradiation, topoisomerase I and II inhibitors, and cisplatin. A similar checkpoint can be demonstrated inp53 ?/? fibroblasts that express p16INK4A. DNA damage-induced G1arrest, which requires the expression of pocket proteins such as Rb, can be abrogated by overexpression of cdk4, kinase-inactive cdk4 variants capable of sequestering p16INK4A, or a cdk4 variant incapable of binding p16INK4A. After exposure to DNA-damaging agents, there was no change either in overall levels of p16INK4A or in amounts of p16INK4A found in complex with cdks 4 and 6. Nonetheless, p16INK4A expression is required for the reduction in cdk4- and cdk6-mediated Rb kinase activity observed in response to DNA damage. During tumor progression, loss of p16INK4A expression may be necessary for cells with wild-type Rb to bypass this G1 arrest checkpoint and attain a fully transformed phenotype.
机译：INK4蛋白家族的成员特异性抑制成视网膜细胞瘤易感基因产物（Rb）的细胞周期蛋白依赖性激酶4（cdk4）和cdk6介导的磷酸化。 p16 INK4A 是一种原型INK4蛋白，已被确定为许多人类癌症中的肿瘤抑制因子。为了使许多恶性细胞类型有效进入S期或逃脱衰老，人们认为需要灭活表达野生型Rb的肿瘤中的p16 INK4A 。在这里，我们证明了通过抑制p16 INK4A 到G 1 停滞检查点响应DNA损伤的另一种肿瘤抑制机制。保留Rb且缺乏p53的Calu-1非小细胞肺癌细胞不会在DNA损伤后停滞在G 1 中。然而，p16 INK4A 的工程表达水平与细胞增殖相适应，可响应γ射线，拓扑异构酶处理恢复G 1 停滞检查点。 I和II抑制剂和顺铂。类似的检查点可以在表达p16 INK4A 的 p53 ？/？成纤维细胞中得到证实。 DNA损伤诱导的G 1 逮捕，需要表达Rb等口袋蛋白，可以通过cdk4的过表达来消除，该蛋白能够隔离p16 INK4A，而激酶无活性cdk4变体 或无法绑定p16 INK4A 的cdk4变体。暴露于DNA破坏剂后，p16 INK4A 的整体水平或p16 INK4A < / sup>与cdks 4和6形成复合体。尽管如此，p16 INK4A 表达对于降低cdk4和cdk6介导的Rb激酶活性是必需的。 DNA损伤。在肿瘤进展期间，可能需要丢失p16 INK4A 表达，以使具有野生型Rb的细胞绕过该G 1 阻滞检查点并获得一个完全转化的表型。

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