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 m echanism of mitotic arrest is transient and implicates a decrease in t he expression of cdc2/cdc28 kinase subunit Homo sapiens 1 (CKsHs1) and a delay in the metabolism of cyclin B. Primary human fibroblasts infe cted with a retroviral vector that drives the expression of a mutant p 53 protein failed to downregulate CKsHs1 expression, degraded cyclin B despite the absence of chromosomal segregation, and underwent DNA end oreduplication. In addition, ectopic expression of CKsHs1 interfered w ith the control of cyclin B metabolism by the mitotic spindle cell cyc le checkpoint and resulted in a higher tendency to undergo DNA endored uplication. These results demonstrate that an altered regulation of CK sHs1 and cyclin B in cells that carry mutant p53 undermines the mitoti c spindle cell cycle checkpoint and facilitates the development of ane uploidy. These data may contribute to the understanding of the origin of heteroploidy in mutant p53 cells.