title: Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation.
abstract: The antimitotic anti-cancer drugs, including taxol, perturb spindle dynamics, and induce prolonged, spindle checkpoint-dependent mitotic arrest in cancer cells. These cells then either undergo apoptosis triggered by the intrinsic mitochondrial pathway or exit mitosis without proper cell division in an adaptation pathway. Using a genome-wide small interfering RNA (siRNA) screen in taxol-treated HeLa cells, we systematically identify components of the mitotic apoptosis and adaptation pathways. We show that the Mad2 inhibitor p31(comet) actively promotes mitotic adaptation through cyclin B1 degradation and has a minor separate function in suppressing apoptosis. Conversely, the pro-apoptotic Bcl2 family member, Noxa, is a critical initiator of mitotic cell death. Unexpectedly, the upstream components of the mitochondrial apoptosis pathway and the mitochondrial fission protein Drp1 contribute to mitotic adaption. Our results reveal crosstalk between the apoptosis and adaptation pathways during mitotic arrest.
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Díaz-Martínez
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Zemfira N
authors.initials: ZN
authors.lastname: Karamysheva
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Warrington
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA hongtao.yu@utsouthwestern.edu.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Yu
mesh_terms: D000222:Adaptation, Physiological; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects*; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D017239:Paclitaxel / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000032:analysis* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D017239:Paclitaxel
keywords: apoptosis; mitochondria; mitosis; mitotic slippage; the spindle checkpoint