title: Role of cyclin B1/Cdc2 in mediating Bcl-XL phosphorylation and apoptotic cell death following nocodazole-induced mitotic arrest.
abstract: Treatment of cancer cells with microtubule inhibitors causes mitotic arrest, which subsequently leads to cell death via activation of the intrinsic apoptotic pathway. Mitotically arrested cells typically display increased phosphorylation (i.e., inactivation) of two key anti-apoptotic proteins, Bcl-2 and Bcl-XL , but the mechanisms that regulate their phosphorylation as well as their role in apoptotic cell death following mitotic arrest are still poorly understood at present, which are the focus of this study. We recently showed that cyclin B1 and cell division cycle 2 (Cdc2) proteins are strongly up-regulated in human breast cancer cells following treatment with nocodazole (a prototypical microtubule inhibitor), and their up-regulation plays a critical role in the development of mitotic prometaphase arrest. In this study, we present evidence showing that the up-regulated cyclin B1/Cdc2 complex in nocodazole-treated human breast cancer cells is also responsible for the increased phosphorylation of Bcl-2 and Bcl-XL . However, only the increased phosphorylation of Bcl-XL , but not the phosphorylation of Bcl-2, contributes to subsequent activation of the intrinsic cell death pathway. In addition, evidence is presented to show that mitotic arrest deficient 2 (MAD2) is a key upstream mediator of the up-regulation of cyclin B1/Cdc2 as well as the subsequent increase in phosphorylationof Bcl-2 and Bcl-XL in nocodazole-treated cancer cells. Together, these results reveal that the up-regulated cyclin B1/Cdc2 complex not only mediates prometaphase arrest in nocodazole-treated cells, but also activates the subsequent intrinsic cell death pathway in these cells via increased phosphorylation of Bcl-XL .
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Hye Joung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Bao Ting
authors.initials: BT
authors.lastname: Zhu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D016203:CDC2 Protein Kinase; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000235:genetics*; D056744:Cyclin B1 / Q000235:genetics*; D018844:Cyclin-Dependent Kinases; D006801:Humans; D061986:MCF-7 Cells; D064246:Mad2 Proteins / Q000235:genetics; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics*; D049468:Prometaphase / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: C494811:BCL2L1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D015739:Nocodazole