Deubiquitinase USP9x Confers Radioresistance through Stabilization of Mcl-1
Deubiquitinase USP9x Confers Radioresistance through Stabilization of Mcl-1
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DOI：
10.1593/neo.12598
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发表时间：
2012-10-01
期刊：
影响因子：
4.8
通讯作者：
Rudner, Justine
中科院分区：
文献类型：
--
作者：
Trivigno, Donatella;Essmann, Frank;Rudner, Justine
髓样细胞白血病序列1（Mcl-1）是Bcl-2家族的抗凋亡成员，通常在肿瘤细胞中过表达，限制了治疗的成功。Mcl-1与其他Bcl-2成员的不同之处在于其高周转率。其表达水平受泛素化和去泛素化酶的严格调节。Mcl-1与Bcl-2家族的某些仅Bcl-2同源结构域3（BH 3）的成员的相互作用可以限制Mcl-1泛素连接酶E3的接近并稳定抗凋亡蛋白。此外，去泛素化酶泛素特异性蛋白酶9 x（USP 9 x）的过表达可通过从Mcl-1去除多聚泛素链防止其蛋白酶体降解而导致Mcl-1的积累。分析辐射诱导的Jurkat细胞凋亡，我们发现，Mcl-1的下调更有效地在敏感的亲本细胞比耐药亚克隆。Mcl-1的下降与细胞死亡诱导和克隆形成存活相关。BH 3-only蛋白Bim、Puma和Noxa的敲低不影响Mcl-1水平或辐射诱导的细胞凋亡。然而，电离辐射导致USP 9 x的激活和增强的抗辐射细胞中Mcl-1的去泛素化，阻止Mcl-1的快速降解。USP 9 x敲低增强了辐射诱导的Mcl-1减少，并使辐射抗性细胞对凋亡诱导敏感，而单独的USP 9 x敲低并不改变未辐射细胞中Mcl-1水平。总之，我们的结果表明，辐射诱导的USP 9 x激活抑制Mcl-1降解和细胞凋亡，从而导致辐射抗性增加。Neoplasia（2012）14，893-904
Myeloid cell leukemia sequence 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, is often overexpressed in tumor cells limiting the therapeutic success. Mcl-1 differs from other Bcl-2 members by its high turnover rate. Its expression level is tightly regulated by ubiquitylating and deubiquitylating enzymes. Interaction of Mcl-1 with certain Bcl-2 homology domain 3 (BH3)-only members of the Bcl-2 family can limit the access to Mcl-1 ubiquitin ligase E3 and stabilizes the antiapoptotic protein. In addition, the overexpression of the deubiquitinase ubiquitin-specific protease 9x (USP9x) can result in the accumulation of Mcl-1 by removing poly-ubiquitin chains from Mcl-1 preventing its proteasomal degradation. Analyzing radiation-induced apoptosis in Jurkat cells, we found that Mcl-1 was down-regulated more efficiently in sensitive parental cells than in a resistant subclone. The decline of Mcl-1 correlated with cell death induction and clonogenic survival. Knockdown of BH3-only proteins Bim, Puma, and Noxa did not affect Mcl-1 level or radiation-induced apoptosis. However, ionizing radiation resulted in activation of USP9x and enhanced deubiquitination of Mcl-1 in the radioresistant cells preventing fast Mcl-1 degradation. USP9x knockdown enhanced radiation-induced decrease of Mcl-1 and sensitized the radioresistant cells to apoptosis induction, whereas USP9x knockdown alone did not change Mcl-1 level in unirradiated cells. Together, our results indicate that radiation-induced activation of USP9x inhibits Mcl-1 degradation and apoptosis resulting in increased radioresistance. Neoplasia (2012) 14, 893-904