Ma Z, Izumi H, Kanai M, Kabuyama Y, Ahn N G, Fukasawa K
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
Oncogene. 2006 Aug 31;25(39):5377-90. doi: 10.1038/sj.onc.1209543. Epub 2006 Apr 17.
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.
中心体异常扩增在人类癌症中普遍存在，是癌细胞有丝分裂缺陷和染色体不稳定的主要原因。与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仅复制一次的机制缺陷会导致中心体异常扩增和有丝分裂缺陷。中心体是无膜细胞器，在中心体复制周期中其组成成分会发生动态变化。通过对未复制和已复制中心体的比较质谱分析，我们鉴定出热休克蛋白家族成员mortalin是一种优先与已复制中心体结合的蛋白质。进一步分析表明，mortalin在中心体复制前的G1晚期定位于中心体，在S期和G2期仍留在中心体，在有丝分裂期间从中心体解离。mortalin的过表达克服了p53对中心体复制的依赖性抑制，并且mortalin驱动的中心体复制需要mortalin与p53之间的物理相互作用。此外，mortalin通过物理相互作用促进p53从中心体解离。缺乏与mortalin结合能力的p53突变体仍留在中心体，并以独立于反式激活功能的方式抑制中心体复制。因此，我们目前的发现不仅将mortalin鉴定为p53的上游分子，还为中心体定位的p53参与中心体复制调控提供了证据。
