MdmX is a substrate for the deubiquitinating enzyme USP2a
MdmX is a substrate for the deubiquitinating enzyme USP2a
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DOI：
10.1038/onc.2009.330
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发表时间：
2010-01-21
期刊：
影响因子：
8
通讯作者：
Saville, M. K.
中科院分区：
文献类型：
--
作者：
Allende-Vega, N.;Sparks, A.;Saville, M. K.
以前的研究表明，泛素特异性蛋白酶2a （USP2a）是Mdm2/p53通路的调节因子。USP2a结合Mdm2，可以使Mdm2去泛素化，而不逆转Mdm2介导的p53泛素化。USP2a过表达导致Mdm2积累，促进p53降解。我们现在证明MdmX也是USP2a的底物。MdmX独立于Mdm2与USP2a结合。异位表达野生型USP2a而非催化突变体可阻止mdm2介导的MdmX降解。这与野生型USP2a去泛素化MdmX的能力有关。在intera -2睾丸胚胎癌细胞和MCF7乳腺癌细胞中，sirna介导的USP2a敲低导致MdmX不稳定，导致MdmX蛋白水平降低，表明内源性USP2a参与了MdmX稳定性的调控。治疗药物顺铂降低MdmX蛋白表达。顺铂暴露后，USP2a mRNA和蛋白水平也降低。USP2a下调的幅度和时间过程表明，顺铂治疗后，USP2a水平的降低可能导致MdmX表达的降低。USP2a的敲低增加了intera -2细胞对顺铂的敏感性，这增加了抑制USP2a联合顺铂可能成为癌症治疗的一种方法的可能性。癌症基因（2010）29,432-441；doi: 10.1038 / onc.2009.330;2009年10月19日在线发布
It has previously been shown that ubiquitin-specific protease 2a (USP2a) is a regulator of the Mdm2/p53 pathway. USP2a binds to Mdm2 and can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination. Overexpression of USP2a causes accumulation of Mdm2 and promotes p53 degradation. We now show that MdmX is also a substrate for USP2a. MdmX associates with USP2a independently of Mdm2. Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2-mediated degradation of MdmX. This correlates with the ability of wild-type USP2a to deubiquitinate MdmX. siRNA-mediated knockdown of USP2a in NTERA-2 testicular embryonal carcinoma cells and MCF7 breast cancer cells causes destabilization of MdmX and results in a decrease in MdmX protein levels, showing that endogenous USP2a participates in the regulation of MdmX stability. The therapeutic drug, cisplatin decreases MdmX protein expression. USP2a mRNA and protein levels were also reduced after cisplatin exposure. The magnitude and time course of USP2a downregulation suggests that the reduction in USP2a levels could contribute to the decrease in MdmX expression following treatment with cisplatin. Knockdown of USP2a increases the sensitivity of NTERA-2 cells to cisplatin, raising the possibility that suppression of USP2a in combination with cisplatin may be an approach for cancer therapy. Oncogene (2010) 29, 432-441; doi:10.1038/onc.2009.330; published online 19 October 2009