Defining the role of BH3-only proteins in mitotic and post-mitotic cell death

定义 BH3-only 蛋白在有丝分裂和有丝分裂后细胞死亡中的作用

• 批准号: 245706574
• 负责人: Professor Dr. Andreas Villunger
• 金额: --
• 依托单位: Division of Developmental Immunology
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245706574?language=en
• 关键词: Defining; role; BH3; only; proteins

Microtubule-targeting agents (MTAs) are standard of care for a number of human malignancies including blood, breast, ovarian and lung cancer. Their mode of action includes prolonged mitotic arrest by interfering with mitotic spindle dynamics that leads to the activation of the spindle assembly checkpoint (SAC). SAC execution involves assembly of the mitotic checkpoint complex (MCC) containing MAD2, Bub3 and BubR1 at kinetochores, driving degradation of the Anaphase-promoting complex (APC) co-activator, CDC20, thereby preventing mitotic exit. Cells stalled in mitosis usually can undergo two different fates, either cell death involving the BH3-only proteins BIM, BID and NOXA that can be paralleled by Ripoptosome activation, or, alternatively, checkpoint adaptation (slippage). The latter occurs when CyclinB levels fall below a critical threshold, due to non-canonical APC-driven protein degradation, that often correlates with a concomitant reduction of pro-apoptotic mediators of the BCL2 family. This leads to premature mitotic exit and escape from apoptosis, often in a polyploid state. Such cells are well known to become genetically instable due to unfaithful segregation of chromosomes leading to chromosomal instability (CIN). The fate of such chromosomally instable (cancer) cells is usually regulated by the tumor suppressor p53 and its activation can either result in post-mitotic cell death, by so-far poorly defined molecular mechanisms (mitotic catastrophe), or cellular senescence. In the absence of p53, such cells can escape these control mechanisms, leading to the creation and expansion of aneuploid clones that form the basis of tumor evolution, progressive disease and ultimately also drug-resistance. The aim of this proposal is to (i) define the mechanisms controlling activity of BH3-only proteins relevant in mitotic and post-mitotic cell death and to (ii) interrogate the contribution of BCL2-regulated cell death in and out of mitosis as a barrier against aneuploidy and cancer.

微管靶向剂（MTA）是许多人类恶性肿瘤（包括血液癌、乳腺癌、卵巢癌和肺癌）的标准治疗。它们的作用模式包括通过干扰有丝分裂纺锤体动力学而延长有丝分裂停滞，从而导致纺锤体组装检查点（SAC）的激活。SAC的执行涉及在着丝粒处组装含有MAD 2、Bub3和BubR1的有丝分裂检查点复合物（MCC），驱动后期促进复合物（APC）共激活剂CDC 20的降解，从而防止有丝分裂退出。在有丝分裂中停滞的细胞通常可以经历两种不同的命运，要么是涉及仅BH3蛋白BIM、BID和NOXA的细胞死亡，其可以通过核糖体激活来终止，或者是检查点适应（滑动）。后者发生在CyclinB水平低于临界阈值时，由于非典型APC驱动的蛋白质降解，这通常与BCL 2家族的促凋亡介质的伴随减少相关。这导致过早的有丝分裂退出和逃避凋亡，通常在多倍体状态。众所周知，这些细胞由于染色体的不忠实分离而变得遗传不稳定，导致染色体不稳定性（CIN）。这种染色体不稳定（癌）细胞的命运通常由肿瘤抑制因子p53调节，其激活可导致有丝分裂后细胞死亡，通过迄今为止定义不清的分子机制（有丝分裂灾难）或细胞衰老。在没有p53的情况下，这些细胞可以逃避这些控制机制，导致非整倍体克隆的产生和扩增，这些克隆形成肿瘤演变、进行性疾病和最终耐药性的基础。该提案的目的是（i）定义控制有丝分裂和有丝分裂后细胞死亡相关的仅BH3蛋白活性的机制，以及（ii）询问BCL 2调节的细胞死亡在有丝分裂中和有丝分裂外作为针对非整倍性和癌症的屏障的贡献。