Centrosome amplification, chromosome instability and cancer development.
During mitosis, two centrosomes form spindle poles and direct the formation of bipolar mitotic spindles, which is an essential event for accurate chromosome segregation into daughter cells. The presence of more than two centrosomes (centrosome amplification), severely disturbs mitotic process and cytokinesis via formation of more than two spindle poles, resulting in an increased frequency of chromosome segregation errors (chromosome instability). Destabilization of chromosomes by centrosome amplification aids acquisition of further malignant phenotypes, hence promoting tumor progression. Centrosome amplification occurs frequently in almost all types of cancer, and is considered as the major contributing factor for chromosome instability in cancer cells. Upon cytokinesis, each daughter cell receives one centrosome, and thus centrosome must duplicate once, and only once, before the next mitosis. If centrosomes duplicate more than once within a single cell cycle, centrosome amplification occurs, which is frequently seen in cells harboring mutations in some tumor suppressor proteins such as p53 and BRCA1. The recent studies have provided critical information for understanding how loss of these proteins allows multiple rounds of centrosome duplication. In this review, how centrosome amplification destabilizes chromosomes, how loss of certain tumor suppressor proteins leads to centrosome amplification, and the role of centrosome amplification in cancer development will be discussed.
Fukasawa
Kenji
K
Department of Cell Biology, University of Cincinnati College of Medicine, P.O. Box 670521 (3125 Eden Ave), Cincinnati, OH 45267-0521, USA. kenji.fukasawa@uc.edu
D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018385:Centrosome / Q000473:pathology* / Q000502:physiology*; D043171:Chromosomal Instability; D048749:Cytokinesis; D004249:DNA Damage; D018450:Disease Progression; D019398:Genes, BRCA1; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D008938:Mitosis; D009369:Neoplasms / Q000503:physiopathology / Q000628:therapy; D010641:Phenotype; D008941:Spindle Apparatus