Rb Regulates DNA Damage Response and Cellular Senescence through E2F-Dependent Suppression of N-Ras Isoprenylation
Rb Regulates DNA Damage Response and Cellular Senescence through E2F-Dependent Suppression of N-Ras Isoprenylation
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DOI：
10.1016/j.ccr.2009.03.001
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发表时间：
2009-04-07
期刊：
影响因子：
50.3
通讯作者：
Takahashi, Chiaki
中科院分区：
文献类型：
--
作者：
Shamma, Awad;Takegami, Yujiro;Takahashi, Chiaki
癌基因诱导的细胞衰老是有据可查的，但很少有人知道如何无限的细胞增殖诱导的肿瘤抑制基因的损失是拮抗细胞功能。Rb杂合子小鼠产生Rb缺陷的C细胞腺瘤，其在N-ras双等位基因缺失后进展为腺癌。在这里，我们表明，pRb失活诱导法呢基二磷酸合酶，许多异戊二烯转移酶，和它们的上游调节固醇调节元件结合蛋白（SREBPs）的表达异常，在E2 F依赖的方式，导致增强异戊二烯化和激活的N-Ras。因此，升高的N-Ras活性诱导Rb缺陷细胞的DNA损伤反应和p130依赖性细胞衰老。此外，Rb杂合子小鼠另外缺乏任何的Ink 4a，Arf，或Suv 39 h1产生C细胞腺癌，表明细胞衰老拮抗Rb缺乏的致癌作用。
Oncogene-induced cellular senescence is well documented, but little is known about how infinite cell proliferation induced by loss of tumor suppressor genes is antagonized by cellular functions. Rb heterozygous mice generate Rb-deficient C cell adenomas that progress to adenocarcinomas following biallelic loss of N-ras. Here, we demonstrate that pRb inactivation induces aberrant expression of farnesyl diphosphate synthase, many prenyltransferases, and their upstream regulators sterol regulatory element-binding proteins (SREBPs) in an E2F-dependent manner, leading to enhanced isoprenylation and activation of N-Ras. Consequently, elevated N-Ras activity induces DNA damage response and p130-dependent cellular senescence in Rb-deficient cells. Furthermore, Rb heterozygous mice additionally lacking any of Ink4a, Arf, or Suv39h1 generated C cell adenocarcinomas, suggesting that cellular senescence antagonizes Rb-deficient carcinogenesis.