title: Cyclin-dependent kinase-1 (Cdk1)/cyclin B1 dictates cell fate after mitotic arrest via phosphoregulation of antiapoptotic Bcl-2 proteins.
abstract: The prevailing model suggests that cell fate after mitotic arrest depends on two independent and competing networks that control cyclin B1 degradation and the generation of death signals. However, recent evidence for Cdk1/cyclin B1-mediated phosphorylation and inactivation of antiapoptotic Bcl-2 proteins suggests the existence of significant cross-talk and interdependence between these pathways. Further, the nature of the mitotic death signals has remained elusive. In this study, we sought to test the hypothesis that fate after mitotic arrest is dictated by the robustness of Cdk1/cyclin B1 signaling to Bcl-2 proteins and to identify signals that may represent a mitotic death signature. We show that when treated with Taxol, slippage-resistant HT29 colon carcinoma cells display robust Cdk1 activity and extensive Mcl-1/Bcl-x(L) phosphorylation and die in mitosis, whereas slippage-prone DLD-1 colon carcinoma cells display weak Cdk1 activity and partial and transient Mcl-1/Bcl-x(L) phosphorylation and die in subsequent interphase or survive. Furthermore, modulation of this signaling axis, either by inhibition of Cdk1 in slippage-resistant HT29 or by enforcing mitotic arrest in slippage-prone DLD-1 cells, evokes a switch in fate, indicating that the strength of Cdk1 signaling to Bcl-2 proteins is a key determinant of outcome. These findings provide novel insight into the pathways that regulate mitotic death, suggest that the robustness of these signaling events may be useful as a marker to define susceptibility to antimitotic drugs, and encourage a revision in the current model describing fate after mitotic arrest.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Sakurikar
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Eichhorn
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Chambers
mesh_terms: D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002470:Cell Survival; D056744:Cyclin B1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence / Q000379:methods; D008938:Mitosis; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D056744:Cyclin B1; D019253:Proto-Oncogene Proteins c-bcl-2; D049452:Green Fluorescent Proteins; D016203:CDC2 Protein Kinase; D017239:Paclitaxel