SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction.
SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction.
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DOI：
10.1038/nature09732
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发表时间：
2011-03-03
期刊：
影响因子：
64.8
通讯作者：
Wei, Wenyi
中科院分区：
文献类型：
--
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
靶向治疗的有效使用在很大程度上取决于应答患者人群的识别。Fbw 7肿瘤抑制因子的缺失经常在各种类型的人类癌症中发现，包括乳腺癌、结肠癌和T细胞急性淋巴细胞白血病（T-ALL）。与这些基因组数据一致，小鼠T细胞中Fbw 7的工程缺失导致T-ALL，验证Fbw 7作为T-ALL肿瘤抑制因子。Fbw 7发挥抗肿瘤活性的精确分子机制仍然是深入研究的领域，并且被认为部分涉及Fbw 7介导的对关键癌症相关蛋白的破坏，所述关键癌症相关蛋白包括c-Jun、c-Myc、细胞周期蛋白E和Notch-1，所有这些蛋白都具有致癌活性并且在包括白血病在内的各种人类癌症中过表达。除了加速细胞生长外，c-Jun、c-Myc或Notch-1的过表达也可引起程序性细胞死亡。因此，相当大的不确定性围绕Fbw 7缺陷细胞如何在上调的c-Jun、c-Myc和/或Notch-1的情况下逃避细胞死亡。在这里，我们报告SCFFbw 7通过靶向促生存Bcl-2家族成员Mcl-1以GSK 3磷酸化依赖的方式进行泛素化和破坏来控制细胞凋亡。人T-ALL细胞系显示Fbw 7缺失与Mcl-1过表达之间存在密切关系。相应地，具有缺陷Fbw 7的T-ALL细胞系对多激酶抑制剂索拉非尼特别敏感，但对Bcl-2拮抗剂ABT-737具有抗性。在遗传水平上，Fbw 7重建或Mcl-1消耗恢复ABT-737敏感性，建立Mcl-1作为Fbw 7缺陷细胞逃避凋亡的治疗相关旁路存活机制。因此，我们的工作为Fbw 7直接肿瘤抑制提供了新的分子见解，直接影响Fbw 7缺陷T-ALL患者的靶向治疗。
The effective use of targeted therapy is highly dependent upon the identification of responder patient populations. Loss of the Fbw7 tumor suppressor is frequently found in various types of human cancers including breast cancer, colon cancer and T-cell acute lymphoblastic leukemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating Fbw7 as a T-ALL tumor suppressor. The precise molecular mechanisms by which Fbw7 exerts anti-tumor activity remain areas of intensive investigation and are thought to relate in part to Fbw7-mediated destruction of key cancer relevant proteins including c-Jun, c-Myc, Cyclin E and Notch-1, all of which possess oncogenic activity and are overexpressed in various human cancers including leukemia. Besides accelerating cell growth, overexpression of either c-Jun, c-Myc or Notch-1 can also provoke programmed cell death. Thus, considerable uncertainty surrounds how Fbw7-deficient cells evade cell death in the setting of upregulated c-Jun, c-Myc and/or Notch-1. Here we report that SCFFbw7 governs cellular apoptosis by targeting the pro-survival Bcl-2 family member, Mcl-1, for ubiquitination and destruction in a GSK3 phosphorylation-dependent manner. Human T-ALL cell lines showed a close relationship between Fbw7 loss and Mcl-1 overexpression. Correspondingly, T-ALL cell lines with defective Fbw7 are particularly sensitive to the multi-kinase inhibitor, sorafenib, but resistant to the Bcl-2 antagonist, ABT-737. On the genetic level, Fbw7 reconstitution or Mcl-1 depletion restores ABT-737 sensitivity, establishing Mcl-1 as a therapeutically relevant bypass survival mechanism for Fbw7-deficient cells to evade apoptosis. Therefore, our work provides novel molecular insight into Fbw7-direct tumor suppression with direct implications for the targeted treatment of Fbw7-deficient T-ALL patients.
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影响因子：
5.3
作者：
Ding, Qingqing;He, Xianghuo;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
15.3
作者：
Onoyama, Ichiro;Tsunematsu, Ryosuke;Nakayama, Keiichi I.
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Nakayama, Keiichi I.
影响因子：
8
作者：
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Adjei, AA
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作者：
Gupta-Rossi, N;Le Bail, O;Israël, A
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Israël, A
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10.5
作者：
Nijhawan, D;Fang, M;Wang, XD
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Wang, XD