Mortalin controls centrosome duplication via modulating centrosomal localization of p53
Mortalin controls centrosome duplication via modulating centrosomal localization of p53
复制标题
DOI：
10.1038/sj.onc.1209543
复制
发表时间：
2006-08-01
期刊：
影响因子：
8
通讯作者：
Fukasawa, K.
中科院分区：
文献类型：
--
作者：
Ma, Z.;Izumi, H.;Fukasawa, K.
在人类癌症中常见的中心体异常扩增是导致癌细胞有丝分裂缺陷和染色体不稳定的主要原因。像DNA一样，中心体在每个细胞周期中复制一次，因此确保中心体在每个细胞周期中复制一次且仅发生一次的机制存在缺陷，导致中心体异常扩增和有丝分裂缺陷。中心体是非膜质细胞器，在中心体复制周期中其成分发生动态变化。通过对未复制和复制中心体的质谱比较分析，我们确定了热休克蛋白家族成员mortalin是一种优先与复制中心体相关的蛋白。进一步分析发现，在G1晚期中心体复制之前，死亡蛋白定位于中心体，在S和G2期间留在中心体，并在有丝分裂期间与中心体分离。过表达的死亡蛋白覆盖了p53依赖的中心体复制抑制，死亡蛋白驱动的中心体复制需要死亡蛋白和p53之间的物理相互作用。此外，死亡素通过物理相互作用促进p53与中心体分离。缺乏与死亡蛋白结合能力的p53突变体保留在中心体上，并以不依赖于交易激活功能的方式抑制中心体复制。因此，我们目前的研究结果不仅确定了mortalin是p53的上游分子，而且为中心体定位的p53参与中心体复制的调控提供了证据。
Abnormal amplification of centrosomes, commonly found in human cancer, is the major cause of mitotic defects and chromosome instability in cancer cells. Like DNA, centrosomes duplicate once in each cell cycle, hence the defect in the mechanism that ensures centrosome duplication to occur once and only once in each cell cycle results in abnormal amplification of centrosomes and mitotic defects. Centrosomes are non-membranous organelles, and undergo dynamic changes in its constituents during the centrosome duplication cycle. Through a comparative mass spectrometric analysis of unduplicated and duplicated centrosomes, we identified mortalin, a member of heat shock protein family, as a protein that associates preferentially with duplicated centrosomes. Further analysis revealed that mortalin localized to centrosomes in late G1 before centrosome duplication, remained at centrosomes during S and G2, and dissociated from centrosomes during mitosis. Overexpression of mortalin overrides the p53-dependent suppression of centrosome duplication, and mortalin-driven centrosome duplication requires physical interaction between mortalin and p53. Moreover, mortalin promotes dissociation of p53 from centrosomes through physical interaction. The p53 mutant that lacks the ability to bind to mortalin remains at centrosomes, and suppresses centrosome duplication in a transactivation function-independent manner. Thus, our present findings not only identify mortalin as an upstream molecule of p53 but also provide evidence for the involvement of centrosomally localized p53 in the regulation of centrosome duplication.