The PIDDosome activates p53 in response to supernumerary centrosomes
The PIDDosome activates p53 in response to supernumerary centrosomes
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DOI：
10.1101/gad.289728.116
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发表时间：
2017-01-01
影响因子：
10.5
通讯作者：
Villunger, Andreas
中科院分区：
文献类型：
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作者：
Fava, Luca L.;Schuler, Fabian;Villunger, Andreas
中心体是动物细胞中主要的微管组织中心，在细胞分裂周期中只复制一次，形成有丝分裂纺锤体的极点。过多的中心体可导致异常的细胞分裂，并与染色体不稳定和癌症有因果关系。在这里，我们报道了成熟中心体数量的增加，通过破坏细胞分裂或强迫中心体过度复制产生，触发PIDDosome多蛋白复合物的激活，导致caspase -2介导的MDM2切割，p53稳定和p21依赖的细胞周期停滞。在肝器官发生过程中，该通路通过调节肝细胞中的p53水平来抑制发育计划的多倍体化程度。综上所述，PIDD小体作为第一道屏障，与p53结合，阻止携带一个以上成熟中心体的细胞增殖，以维持基因组的完整性。
Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDD osome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.