Function of Nucleophosmin/B23 in Centrosome Duplication

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DESCRIPTION (provided by applicant): Chromosome instability is a formidable force in the multi-step carcinogenesis by facilitating the accumulation of genetic lesions required for the acquisition of malignant phenotypes. During last several years, there is an accumulation of evidence that abnormal amplification of centrosomes due to the deregulated duplication of centrosomes is common in human tumors. A deleterious consequence of centrosome hyperamplification is featured during mitosis by the formation of aberrant spindles organized by multiple spindle poles, leading to an increased frequency of chromosome segregation errors. Thus, centrosome hyperamplification is one major factor that contributes to chromosome instability in human cancers. Centrosome duplication is triggered by cyclin-dependent kinase (CDK)2/cyclin E (and/or cyclin A) in a kinase activity-dependent manner. Because CDK2/cyclin E also drives cells to initiate DNA synthesis, the temporal activation of CDK2/cyclin E occurring in the mid-late G1 is believed to coordinate centrosome duplication and other cell cycle events, including DNA replication. We have recently found that nucleophosmin (NPM)/B23 is a key centrosomal target of CDK2 in the initiation of centrosome duplication. NPM/B23 is directly phosphorylated by CDK2/cyclin E, and dissociates from the centrosomes upon CDK2/cyclin E-mediated phosphorylation. Microinjection of anti-NPM/B23 antibody as well as expression of a dominant negative NPM/B23 inhibits centrosome duplication. These results suggest that dissociation of centrosomal NPM/B23 induced by CDK2-mediated phosphorylation is a critical event for the initiation of centrosome duplication, constituting a licensing system for centrosome duplication, ensuring the coordination of centrosome and DNA duplication as well as restricting centrosome duplication to occur once within a single cell cycle. Elucidation of the functional role of NPM/B23 in centrosome duplication, especially in association with CDK2/cyclin E (and cyclin A), at a molecular level will provide crucial information for further understanding of the regulation of centrosome duplication, which leads to the potential of designing effective cancer intervention protocols targeting centrosome duplication. Such an approach may prove effective, since centrosome duplication, like DNA replication, is restricted to proliferating cells. Moreover, blocking the centrosome duplication process results in suppression of chromosome instability as well as cell division.