Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation

Laura A Díaz-Martínez; Zemfira N Karamysheva; Ross Warrington; Bing Li; Shuguang Wei; Xian-Jin Xie; Michael G Roth; Hongtao Yu

doi:10.15252/embj.201487826

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Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation

Journal article

Open access

Peer reviewed

Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation

Laura A Díaz-Martínez, Zemfira N Karamysheva, Ross Warrington, Bing Li, Shuguang Wei, Xian-Jin Xie, Michael G Roth and Hongtao Yu

The EMBO journal, Vol.33(17), pp.1960-1976

09/01/2014

DOI: 10.15252/embj.201487826

PMCID: PMC4195789

PMID: 25024437

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https://europepmc.org/articles/pmc4195789View

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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.

Mitosis

Apoptosis

Adaptation, Physiological

RNA, Small Interfering - genetics

Paclitaxel - pharmacology

Epithelial Cells - drug effects

Humans

Antineoplastic Agents - pharmacology

Gene Expression Profiling

RNA, Small Interfering - analysis

HeLa Cells

Epithelial Cells - cytology

Details

Title: Subtitle: Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation
Creators: Laura A Díaz-Martínez - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
Zemfira N Karamysheva - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
Ross Warrington - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
Bing Li - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
Shuguang Wei - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
Xian-Jin Xie - Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX, USA
Michael G Roth - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
Hongtao Yu - Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA hongtao.yu@utsouthwestern.edu
Resource Type: Journal article
Publication Details: The EMBO journal, Vol.33(17), pp.1960-1976
DOI: 10.15252/embj.201487826
PMID: 25024437
PMCID: PMC4195789
NLM abbreviation: EMBO J
ISSN: 1460-2075
eISSN: 1460-2075
Publisher: England
Grant note: R01CA125269 / NCI NIH HHS R01 CA125269 / NCI NIH HHS Howard Hughes Medical Institute
Language: English
Date published: 09/01/2014
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917771802771

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