PDF(Pubmed)
Abstract：
Interference with microtubule dynamics in mitosis activates the spindle assembly checkpoint (SAC) to prevent chromosome segregation errors. The SAC induces mitotic arrest by inhibiting the anaphase-promoting complex (APC) via the mitotic checkpoint complex (MCC). The MCC component MAD2 neutralizes the critical APC cofactor, CDC20, preventing exit from mitosis. Extended mitotic arrest can promote mitochondrial apoptosis and caspase activation. However, the impact of mitotic cell death on tissue homeostasis in vivo is ill-defined. By conditional MAD2 overexpression, we observe that chronic SAC activation triggers bone marrow aplasia and intestinal atrophy in mice. While myelosuppression can be compensated for, gastrointestinal atrophy is detrimental. Remarkably, deletion of pro-apoptotic Bim/Bcl2l11 prevents gastrointestinal syndrome, while neither loss of Noxa/Pmaip or co-deletion of Bid and Puma/Bbc3 has such a protective effect, identifying BIM as rate-limiting apoptosis effector in mitotic cell death of the gastrointestinal epithelium. In contrast, only overexpression of anti-apoptotic BCL2, but none of the BH3-only protein deficiencies mentioned above, can mitigate myelosuppression. Our findings highlight tissue and cell-type-specific survival dependencies in response to SAC perturbation in vivo.
摘要：
干扰有丝分裂中的微管动力学会激活纺锤体组装检查点（SAC），以防止染色体分离错误。SAC通过经由有丝分裂检查点复合物(MCC)抑制后期促进复合物(APC)来诱导有丝分裂阻滞。MCC成分MAD2中和关键的APC辅因子，CDC20，防止退出有丝分裂。延长有丝分裂阻滞可促进线粒体凋亡和caspase激活。然而,有丝分裂细胞死亡对体内组织稳态的影响尚不明确。通过条件性MAD2过表达，我们观察到慢性SAC激活引发小鼠骨髓发育不全和肠萎缩。虽然骨髓抑制可以得到补偿，胃肠萎缩是有害的。值得注意的是,促凋亡Bim/Bcl2l11的缺失可预防胃肠道综合征，虽然失去Noxa/Pmaip或共同删除Bid和Puma/Bbc3都没有这种保护作用，鉴定BIM作为胃肠上皮有丝分裂细胞死亡的限速凋亡效应。相比之下,仅过度表达抗凋亡BCL2，但没有上述仅BH3蛋白缺陷，可以减轻骨髓抑制。我们的发现强调了体内对SAC扰动的组织和细胞类型特异性存活依赖性。
