cIAP2 represses IKKα/β-mediated activation of MDM2 to prevent p53 degradation
cIAP2 represses IKKα/β-mediated activation of MDM2 to prevent p53 degradation
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DOI：
10.4161/cc.22223
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发表时间：
2012-11-01
期刊：
影响因子：
4.3
通讯作者：
Pratt, M. A. Christine
中科院分区：
文献类型：
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作者：
Lau, Rosanna;Niu, Min Ying;Pratt, M. A. Christine
细胞凋亡抑制蛋白（cIAP 1和cIAP 2）的功能是防止细胞凋亡，并经常在各种癌症中过度表达。然而，cIAP 1/2突变可通过IB α-激酶-α（IKK α）激活替代NF κ B通路，并与造血系统恶性肿瘤相关。在目前的研究中，我们发现，在人乳腺上皮细胞中敲低cIAP 2，通过增加SUMO化和大幅减少未在Ser 166磷酸化的MDM 2库，导致MDM 2活化。cIAP 2 siRNA显著降低了p53水平，这通过添加MDM 2抑制剂Nutlin 3a来挽救。诱导cIAP降解的IAP拮抗剂瞬时增加MDM 2 mRNA。同时转染cIAP 2和IKKa的siRNA减少了MDM 2蛋白，而激酶死亡的IKK β的表达强烈增加了非Ser 166 P-MDM 2。抑制IKK α或IKK β部分挽救了p53水平，而伴随的IKK α/β抑制在cIAP 2敲低后完全挽救了p53。令人惊讶的是，IKK α敲低单独增加SUMO-MDM 2，表明在没有激活的情况下，IKK α可以阻止MDM 2 SUMO化。cIAP 2敲低破坏了MDM 2 SUMO连接酶、PIAS 1和IKK α之间的相互作用。cIAP 2的部分敲除与H-V12-ras转染的乳腺上皮细胞协同作用以增强集落形成。总之，我们的数据确定了cIAP 2在维持野生型p53水平中的新作用，其通过阻止NF κ B介导的增加和IKK α/-β依赖性的MDM 2转录和翻译后修饰。因此，cIAP 2的突变或减少可能部分通过下调p53促进癌症的发生。
Cellular inhibitor of apoptosis proteins (cIAP1 and cIAP2) function to prevent apoptosis and are often overexpressed in various cancers. However, mutations in cIAP1/2 can activate the alternative NF kappa B pathway through IB alpha-kinase-alpha (IKK alpha) and are associated with hematopoetic malignancies. In the current study, we found that knockdown of cIAP2 in human mammary epithelial cells resulted in activation of MDM2 through increased SUMOylation and profound reduction of the pool of MDM2 not phosphorylated at Ser166. cIAP2 siRNA markedly decreased p53 levels, which were rescued by addition of the MDM2 inhibitor, Nutlin3a. An IAP antagonist, which induces cIAP degradation, transiently increased MDM2 mRNA. Simultaneous transfection of siRNA for cIAP2 and IKKa reduced MDM2 protein, while expression of a kinase-dead IKK beta strongly increased non-Ser166 P-MDM2. Inhibition of either IKK alpha or -beta partially rescued p53 levels, while concomitant IKK alpha/beta inhibition fully rescued p53 after cIAP2 knockdown. Surprisingly, IKK alpha knockdown alone increased SUMO-MDM2, suggesting that in the absence of activation, IKK alpha can prevent MDM2 SUMOylation. cIAP2 knockdown disrupted the interaction between the MDM2 SUMO ligase, PIAS1 and IKK alpha. Partial knockdown of cIAP2 cooperated with H-V12-ras-transfected mammary epithelial cells to enhance colony formation. In summary, our data identify a novel role for cIAP2 in maintaining wild-type p53 levels by preventing both an NF kappa B-mediated increase and IKK alpha/-beta-dependent transcriptional and post-translational modifications of MDM2. Thus, mutations or reductions in cIAP2 could contribute to cancer promotion, in part, through downregulation of p53.