Mortalin controls centrosome duplication via modulating centrosomal localization of p53.
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.
Ma
Z
Z
Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
Izumi
H
H
Kanai
M
M
Kabuyama
Y
Y
Ahn
N G
NG
Fukasawa
K
K
D002453:Cell Cycle; D018385:Centrosome / Q000648:ultrastructure*; D002999:Clone Cells; D016193:G1 Phase; D016195:G2 Phase; D016158:Genes, p53; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D016196:S Phase; D014158:Transcription, Genetic
D018840:HSP70 Heat-Shock Proteins; C080352:mortalin