Ras Regulates Rb via NORE1A
Ras Regulates Rb via NORE1A
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DOI：
10.1074/jbc.m115.697557
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发表时间：
2016-02-05
影响因子：
4.8
通讯作者：
Clark, Geoffrey J.
中科院分区：
文献类型：
--
作者：
Barnoud, Thibaut;Donninger, Howard;Clark, Geoffrey J.
Ras癌基因突变是人类癌症中最常见的事件之一。虽然Ras调节许多促进生长的途径来驱动转化，但它可以矛盾地促进被称为癌基因诱导的衰老的不可逆细胞周期停滞。虽然衰老已被明确地牵连作为一个主要的防御机制，对肿瘤发生，Ras可以促进这样的衰老表型的机制仍然不清楚。我们最近已经表明，Ras死亡效应NORE1A在促进Ras诱导的衰老中起着关键作用，并将Ras与p53肿瘤抑制因子的调节联系起来。我们现在发现NORE1A也将Ras与第二个主要的衰老肿瘤抑制因子视网膜母细胞瘤（Rb）蛋白的调节联系起来。我们发现Ras诱导NORE1A和磷酸酶PP1A之间形成复合物，通过去磷酸化促进Rb肿瘤抑制因子的激活。此外，Rb的抑制降低NORE1A衰老活性。这些结果，加上我们以前的研究结果，表明NORE1A作为一个关键的肿瘤抑制节点，连接Ras到p53和Rb途径，以驱动衰老。
Mutations in the Ras oncogene are one of the most frequent events in human cancer. Although Ras regulates numerous growth-promoting pathways to drive transformation, it can paradoxically promote an irreversible cell cycle arrest known as oncogene-induced senescence. Although senescence has clearly been implicated as a major defense mechanism against tumorigenesis, the mechanisms by which Ras can promote such a senescent phenotype remain poorly defined. We have shown recently that the Ras death effector NORE1A plays a critical role in promoting Ras-induced senescence and connects Ras to the regulation of the p53 tumor suppressor. We now show that NORE1A also connects Ras to the regulation of a second major prosenescent tumor suppressor, the retinoblastoma (Rb) protein. We show that Ras induces the formation of a complex between NORE1A and the phosphatase PP1A, promoting the activation of the Rb tumor suppressor by dephosphorylation. Furthermore, suppression of Rb reduces NORE1A senescence activity. These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node, linking Ras to both the p53 and the Rb pathways to drive senescence.