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• W2099682050 abstract "ABSTRACT During a normal cell cycle, entry into S phase is dependent on completion of mitosis and subsequent activation of cyclin-dependent kinases (Cdks) in G 1 . These events are monitored by checkpoint pathways. Recent studies and data presented herein show that after treatment with microtubule inhibitors (MTIs), cells deficient in the Cdk inhibitor p21 Waf1/Cip1 enter S phase with a ≥4 N DNA content, a process known as endoreduplication, which results in polyploidy. To determine how p21 prevents MTI-induced endoreduplication, the G 1 /S and G 2 /M checkpoint pathways were examined in two isogenic cell systems: HCT116 p21 +/+ and p21 −/− cells and H1299 cells containing an inducible p21 expression vector (HIp21). Both HCT116 p21 −/− cells and noninduced HIp21 cells endoreduplicated after MTI treatment. Analysis of G 1 -phase Cdk activities demonstrated that the induction of p21 inhibited endoreduplication through direct cyclin E/Cdk2 regulation. The kinetics of p21 inhibition of cyclin E/Cdk2 activity and binding to proliferating-cell nuclear antigen in HCT116 p21 +/+ cells paralleled the onset of endoreduplication in HCT116 p21 −/− cells. In contrast, loss of p21 did not lead to deregulated cyclin D1-dependent kinase activities, nor did p21 directly regulate cyclin B1/Cdc2 activity. Furthermore, we show that MTI-induced endoreduplication in p53-deficient HIp21 cells was due to levels of p21 protein below a threshold required for negative regulation of cyclin E/Cdk2, since ectopic expression of p21 restored cyclin E/Cdk2 regulation and prevented endoreduplication. Based on these findings, we propose that p21 plays an integral role in the checkpoint pathways that restrain normal cells from entering S phase after aberrant mitotic exit due to defects in microtubule dynamics." @default.
• W2099682050 created "2016-06-24" @default.
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• W2099682050 date "1999-01-01" @default.
• W2099682050 modified "2023-10-11" @default.
• W2099682050 title "p21^Waf1/Cip1 Inhibition of Cyclin E/Cdk2 Activity Prevents Endoreduplication after Mitotic Spindle Disruption" @default.
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• W2099682050 doi "https://doi.org/10.1128/mcb.19.1.205" @default.
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