Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

摘要: Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol vincristine prescribed widely for various malignancies, including ovarian breast adenocarcinomas, non-small-cell lung cancer, leukaemias lymphomas. These arrest cells mitosis subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour use to evade induced by also unclear. Here we show the pro-survival protein MCL1 (ref. 3) is a crucial regulator apoptosis triggered During mitotic arrest, levels decline markedly, post-translational mechanism, potentiating death. Phosphorylation directs its interaction with tumour-suppressor FBW7, which substrate-binding component ubiquitin ligase complex. polyubiquitylation then it proteasomal degradation. degradation was blocked patient-derived lacked FBW7 or had loss-of-function mutations conferring resistance promoting chemotherapeutic-induced polyploidy. Additionally, primary samples were enriched inactivation elevated levels, underscoring prominent these proteins oncogenesis. Our findings suggest profiling status tumours, terms messenger RNA genetic status, could be useful predict response patients