Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression.
Centrosome hyperamplification and the consequential mitotic defects contribute to chromosome instability in cancers. Loss or mutational inactivation of p53 has been shown to induce chromosome instability through centrosome hyperamplification. It has recently been found that Cdk2-cyclin E is involved in the initiation of centrosome duplication, and that constitutive activation of Cdk2-cyclin E results in the uncoupling of the centrosome duplication cycle and the DNA replication cycle. Cyclin E overexpression and p53 mutations occur frequently in tumors. Here, we show that cyclin E overexpression and loss of p53 synergistically increase the frequency of centrosome hyperamplification in cultured cells as well as in tumors developed in p53-null, heterozygous, and wildtype mice. Through examination of cells derived from Waf1-null mice, we further found that Waf1, a potent inhibitor of Cdk2-cyclin E and a major target of p53's transactivation function, is involved in coordinating the initiation of centrosome duplication and DNA replication, suggesting that Waf1 may act as a molecular link between p53 and Cdk2-cyclin E in the control of the centrosome duplication cycle.
Mussman
J G
JG
Department of Cell Biology, University of Cincinnati College of Medicine, OH 45267-0521, USA.
Horn
H F
HF
Carroll
P E
PE
Okuda
M
M
Tarapore
P
P
Donehower
L A
LA
Fukasawa
K
K
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002478:Cells, Cultured; D018385:Centrosome / Q000502:physiology*; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D016213:Cyclins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004261:DNA Replication / Q000502:physiology; D004789:Enzyme Activation; D005347:Fibroblasts; D016158:Genes, p53; D005838:Genotype; D019656:Loss of Heterozygosity; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009363:Neoplasm Proteins / Q000032:analysis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D014404:Tubulin / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases