Spy1 induces de-ubiquitinating of RIP1 arrest and confers glioblastoma's resistance to tumor necrosis factor (TNF-α)-induced apoptosis through suppressing the association of CLIPR-59 and CYLD
Spy1 induces de-ubiquitinating of RIP1 arrest and confers glioblastoma's resistance to tumor necrosis factor (TNF-α)-induced apoptosis through suppressing the association of CLIPR-59 and CYLD
复制标题
Spy1 诱导 RIP1 阻滞去泛素化，并通过抑制 CLIPR-59 和 CYLD 的关联，赋予胶质母细胞瘤对肿瘤坏死因子 (TNF-α) 诱导的细胞凋亡的抵抗力
DOI：
10.1080/15384101.2015.1041688
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发表时间：
2015-07-03
期刊：
影响因子：
4.3
通讯作者：
Shen, Aiguo
中科院分区：
文献类型：
--
作者：
Ding, Zongmei;Liu, Yonghua;Shen, Aiguo
多形性胶质母细胞瘤（GBM）是一种IV级胶质瘤，对TNF诱导的细胞凋亡具有抗性。CLIPR-59调节RIP 1的泛素化，从而促进Caspase-8活化以通过TNF-α诱导细胞凋亡。在这里，我们报道了CLIPR-59在GBM细胞和高级别胶质瘤肿瘤样本中下调，这与无癌生存率降低相关。在GBM细胞中，CLIPR-59与Spy 1相互作用，导致其与去泛素化酶CYLD的结合减少。此外，实验性降低Spy 1水平降低GBM细胞活力，同时通过增强GBM中CLIPR-59和CYLD的结合能力来增加RIP 1的赖氨酸-63依赖性去泛素化活性，从而促进Caspase-8和Caspase-3活化以诱导TNF-α诱导的细胞凋亡。这些发现已经确定了一种新的Spy 1-CLIPR-59在GBM细胞对TNF-诱导的凋亡的抵抗中的相互作用，揭示了恶性脑肿瘤干预中的潜在靶点。
Glioblastoma multiforme (GBM), a grade-IV glioma, is resistant to TNF- induced apoptosis. CLIPR-59 modulates ubiquitination of RIP1, thus promoting Caspase-8 activation to induce apoptosis by TNF-. Here we reported that CLIPR-59 was down-regulated in GBM cells and high-grade glioma tumor samples, which was associated with decreased cancer-free survival. In GBM cells, CLIPR-59 interacts with Spy1, resulting in its decreased association with CYLD, a de-ubiquitinating enzyme. Moreover, experimental reduction of Spy1 levels decreased GBM cells viability, while increased the lysine-63-dependent de-ubiquitinating activity of RIP1 via enhancing the binding ability of CLIPR-59 and CYLD in GBM, thus promoting Caspase-8 and Caspase-3 activation to induce apoptosis by TNF-. These findings have identified a novel Spy1-CLIPR-59 interplay in GBM cell's resistance to TNF--induced apoptosis revealing a potential target in the intervention of malignant brain tumors.