Mdm2 and tumorigenesis: evolving theories and unsolved mysteries.
Mdm2 and tumorigenesis: evolving theories and unsolved mysteries.
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DOI：
10.1177/1947601912457368
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发表时间：
2012-03
期刊：
影响因子：
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通讯作者：
Emir Senturk;J. Manfredi
中科院分区：
文献类型：
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作者：
Emir Senturk;J. Manfredi
自从发现Mdm 2以来，这种RING E3泛素连接酶对癌症病理学的贡献几乎完全集中在其作为p53肿瘤抑制因子的负调节剂的作用上。在正常条件下，Mdm 2促进p53的泛素和蛋白酶体依赖性降解。因此，p53的水平保持足够低，以允许细胞存活和细胞周期进展。然而，在DNA损伤或核糖体应激等损伤的情况下，Mdm 2-p53相互作用被破坏，p53被稳定。p53激活的无数细胞内结果共同构成了一个强大的肿瘤抑制程序，但在癌症中却出现了短路。已知超过一半的人类恶性肿瘤失去了p53表达或持续p53突变，而许多剩余的肿瘤在p53活性的关键介质中具有其他改变，包括Mdm 2的过表达。靶向Mdm 2和p53之间相互作用的疗法代表了在后一种情况下重新激活p53通路的可能手段。然而，p53丢失或Mdm 2过表达的生物学后果的重叠程度尚未得到彻底研究。事实上，Mdm 2的几种p53非依赖性功能的证据表明，破坏Mdm 2-p53相互作用可能无法解决过表达Mdm 2的肿瘤特异性致癌作用的全谱。
Since the discovery of Mdm2, the contribution of this RING E3 ubiquitin ligase to the pathobiology of cancer has focused almost exclusively on its role as a negative regulator of the p53 tumor suppressor. Under normal conditions, Mdm2 promotes the ubiquitin- and proteasome-dependent degradation of p53. Levels of p53 are thus kept sufficiently low to allow for cell survival and cell cycle progression. In the context of such insults as DNA damage or ribosomal stress, however, the Mdm2-p53 interaction is disrupted and p53 is stabilized. The myriad intracellular outcomes of p53 activation together comprise a robust program of tumor suppression that is short-circuited in cancer. Over half of all human malignancies are known to have lost p53 expression or sustained p53 mutation, whereas many of the remaining tumors harbor other alterations in key mediators of p53 activity that include overexpression of Mdm2. Therapies targeting the interaction between Mdm2 and p53 represent a possible means of pharmacologically reactivating the p53 pathway in this latter setting. The degree of overlap across the biological consequences of either p53 loss or Mdm2 overexpression, however, has not been thoroughly explored. Indeed, a body of evidence for several p53-independent functions of Mdm2 suggests that disrupting the Mdm2-p53 interaction may fail to address the full spectrum of oncogenic effects specific to tumors that overexpress Mdm2.