The role of p21Cip1/Waf1 and CDK2/cyclin E in regulating centrosome duplication.

摘要

The centrosome plays an important role in directing the formation of the bipolar spindle during mitosis, a process that ensures the accurate segregation of chromosomes to daughter cells. Because of its importance in mitosis, centrosome duplication is highly controlled, and is under many of the same constraints as DNA replication. Duplication of both is initiated concomitantly, both initiate duplication in response to activation of cyclin-dependent kinase 2/cyclin E (CDK2/CycE), and the reduplication within the same cell cycle is suppressed in both. Many tumors exhibit an abnormal number of centrosomes, indicative of the loss of these regulatory mechanisms. The functional loss of the tumor suppressor p53 is one of the most common occurrences in tumor formation, and p53 has been shown to play an important role in regulating centrosome duplication by promoting proper initiation of centrosome duplication as well as by suppressing reduplication. CDK2/CycE has also been shown to play an important role in initiating centrosome duplication, and the centrosome hyperamplification of many tumors can be linked to a constitutive activation of this kinase complex. We have shown that the loss of p53 induces centrosome hyperamplification in both cultured cells as well as in spontaneously formed rodent tumors synergistically with the constitutive activation of CDK2/CycE. We have shown that p21Cip1/Waf1 (p21) plays an important role in coordinating the initiation of centrosome duplication with the initiation of DNA synthesis, and p21-null cells initiate centrosome duplication before initiation of DNA synthesis. We have also identified nucleophosmin (NPM) as a centrosomal target of CDK2/CycE, and have shown that the phosphorylation of NPM by CDK2/CycE is a necessary event for centrosome duplication. And finally, we have identified a novel interaction between the Mitogen Activated Protein Kinase (MAPK) and p21. The MAPK-mediated phosphorylation of p21 promotes nuclear localization of p21, at least in part by mediating an increase interaction between p21 and the nuclear import factor karyopherin alpha1. The MAPK-p21 interaction may have interesting implications for the regulation of centrosome duplication as well as for the migration of centrosomes to the spindle poles.