NORE1A Regulates MDM2 Via β-TrCP.
NORE1A Regulates MDM2 Via β-TrCP.
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DOI：
10.3390/cancers8040039
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发表时间：
2016-03-23
期刊：
影响因子：
5.2
通讯作者：
Clark GJ
中科院分区：
文献类型：
--
作者：
Schmidt ML;Calvisi DF;Clark GJ
小鼠双微体2同源物（MDM 2）是主肿瘤抑制因子p53的关键负调节因子。MDM 2在多个水平上调节p53，包括作为蛋白质的泛素连接酶，从而促进其被蛋白酶体降解。MDM 2是致癌的，并且经常被发现在人类肿瘤中过表达，这表明其失调在人类癌症中起重要作用。我们最近发现Ras效应子和RASSF（Ras关联结构域家族）家族成员RASSF 5/NORE 1A增强核p53的水平。我们还发现NORE 1A（Novel Ras Effector 1A）结合SCF-泛素连接酶复合物β-TrCP的底物识别组分。在这里，我们现在表明NORE 1A通过SCF-β-TrCP靶向其泛素化来调节MDM 2蛋白水平。我们还表明NORE 1A蛋白水平的抑制增强了MDM 2蛋白的表达。最后，我们发现MDM 2可以抑制NORE 1A过表达诱导的有效衰老表型。因此，我们确定了Ras/NORE 1A可以调节p53蛋白水平的机制。由于MDM 2除了p53之外还有几个重要的靶点，这一发现对由于启动子甲基化而失去NORE 1A表达的肿瘤细胞中的癌症生物学具有广泛的意义。
Mouse Double Minute 2 Homolog (MDM2) is a key negative regulator of the master tumor suppressor p53. MDM2 regulates p53 on multiple levels, including acting as an ubiquitin ligase for the protein, thereby promoting its degradation by the proteasome. MDM2 is oncogenic and is frequently found to be over-expressed in human tumors, suggesting its dysregulation plays an important role in human cancers. We have recently found that the Ras effector and RASSF (Ras Association Domain Family) family member RASSF5/NORE1A enhances the levels of nuclear p53. We have also found that NORE1A (Novel Ras Effector 1A) binds the substrate recognition component of the SCF-ubiquitin ligase complex β-TrCP. Here, we now show that NORE1A regulates MDM2 protein levels by targeting it for ubiquitination by SCF-β-TrCP. We also show the suppression of NORE1A protein levels enhances MDM2 protein expression. Finally, we show that MDM2 can suppress the potent senescence phenotype induced by NORE1A over-expression. Thus, we identify a mechanism by which Ras/NORE1A can modulate p53 protein levels. As MDM2 has several important targets in addition to p53, this finding has broad implications for cancer biology in tumor cells that have lost expression of NORE1A due to promoter methylation.