The role of the NORE1A tumor suppressor in Oncogene-Induced Senescence.
The role of the NORE1A tumor suppressor in Oncogene-Induced Senescence.
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DOI：
10.1016/j.canlet.2017.04.030
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发表时间：
2017-08-01
期刊：
影响因子：
9.7
通讯作者：
Clark GJ
中科院分区：
文献类型：
--
作者：
Barnoud T;Schmidt ML;Donninger H;Clark GJ
Ras基因是人类癌症中最常突变的癌基因。然而，Ras生物学是相当复杂的。虽然Ras通过调节许多生长促进途径促进肿瘤发生，但自相矛盾的是，活化的Ras也可导致细胞周期停滞、死亡和癌基因诱导的衰老（OIS）。OIS被认为是保护细胞免受异常Ras信号传导的关键途径。多个报道强调了p53和Rb肿瘤抑制因子在Ras介导的OIS中的重要性。然而，直到最近，连接Ras与这些蛋白质的分子机制仍然未知。RASSF家族的肿瘤抑制因子最近已被确定为Ras的直接效应子。其中一个成员NORE1A（RASSF5）可能是Ras诱导的衰老与p53和Rb调控之间缺失的环节。这通过促进蛋白质稳定性而定量地发生，以及通过促进关键的促衰老翻译后修饰而定性地发生。在这里，我们回顾了NORE1A可以激活OIS作为Ras介导的转化的屏障的机制，以及这如何导致对NORE1A表达缺失的癌症的治疗策略的改进。
The Ras genes are the most frequently mutated oncogenes in human cancer. However, Ras biology is quite complex. While Ras promotes tumorigenesis by regulating numerous growth promoting pathways, activated Ras can paradoxically also lead to cell cycle arrest, death, and Oncogene-Induced Senescence (OIS). OIS is thought to be a critical pathway that serves to protect cells against aberrant Ras signaling. Multiple reports have highlighted the importance of the p53 and Rb tumor suppressors in Ras mediated OIS. However, until recently, the molecular mechanisms connecting Ras to these proteins remained unknown. The RASSF family of tumor suppressors has recently been identified as direct effectors of Ras. One of these members, NORE1A (RASSF5), may be the missing link between Ras-induced senescence and the regulation of p53 and Rb. This occurs both quantitatively, by promoting protein stability, as well as qualitatively via promoting critical pro-senescent post-translational modifications. Here we review the mechanisms by which NORE1A can activate OIS as a barrier against Ras-mediated transformation, and how this could lead to improved therapeutic strategies against cancers having lost NORE1A expression.
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