Ectopic expression of cdc2/cdc28 kinase subunit Homo sapiens 1 uncouples cyclin B metabolism from the mitotic spindle cell cycle checkpoint.
Primary human fibroblasts arrest growth in response to the inhibition of mitosis by mitotic spindle-depolymerizing drugs. We show that the mechanism of mitotic arrest is transient and implicates a decrease in the expression of cdc2/cdc28 kinase subunit Homo sapiens 1 (CKsHs1) and a delay in the metabolism of cyclin B. Primary human fibroblasts infected with a retroviral vector that drives the expression of a mutant p53 protein failed to downregulate CKsHs1 expression, degraded cyclin B despite the absence of chromosomal segregation, and underwent DNA endoreduplication. In addition, ectopic expression of CKsHs1 interfered with the control of cyclin B metabolism by the mitotic spindle cell cycle checkpoint and resulted in a higher tendency to undergo DNA endoreduplication. These results demonstrate that an altered regulation of CKsHs1 and cyclin B in cells that carry mutant p53 undermines the mitotic spindle cell cycle checkpoint and facilitates the development of aneuploidy. These data may contribute to the understanding of the origin of heteroploidy in mutant p53 cells.
Department of Physiology & Biophysics and Ireland Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
M L
ML
Hixon
A I
AI
Flores
M W
MW
Wagner
A
A
Gualberto
D016203:CDC2 Protein Kinase / Q000502:physiology; D042846:CDC2-CDC28 Kinases; D017489:CDC28 Protein Kinase, S cerevisiae / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D019926:Cyclin B / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases; D004261:DNA Replication / Q000235:genetics; D005347:Fibroblasts; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics; D005814:Genes, Viral / Q000235:genetics; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D027383:Papillomaviridae / Q000235:genetics; D011003:Ploidies; D011494:Protein Kinases; D012333:RNA, Messenger / Q000378:metabolism; D008941:Spindle Apparatus / Q000502:physiology*; D014162:Transfection / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C093090:CKS1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019926:Cyclin B; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D017489:CDC28 Protein Kinase, S cerevisiae; D018844:Cyclin-Dependent Kinases