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MISSION LentiPlex Pooled shRNA Library Screening in Mammalian Cells
Published on: December 21, 2011
Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation
Laura A Díaz-Martínez1, Zemfira N Karamysheva1, Ross Warrington1
1Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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.
Insights
Anti-cancer drugs like taxol cause mitotic arrest. This study identifies key players in cancer cell apoptosis and adaptation pathways, revealing crosstalk between them.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Antimitotic drugs, such as taxol, disrupt spindle dynamics, leading to mitotic arrest in cancer cells.
- Cancer cells in mitotic arrest can undergo apoptosis or adapt and exit mitosis without proper division.
Purpose of the Study:
- To systematically identify components of the mitotic adaptation and apoptosis pathways using a genome-wide screen.
- To elucidate the roles of specific proteins, including p31(comet) and Noxa, in these pathways.
Main Methods:
- Genome-wide small interfering RNA (siRNA) screen in taxol-treated HeLa cells.
- Analysis of protein degradation (cyclin B1) and apoptotic signaling.
Main Results:
- p31(comet) promotes mitotic adaptation via cyclin B1 degradation and has a minor role in suppressing apoptosis.
- Noxa is crucial for initiating mitotic cell death.
- Unexpectedly, mitochondrial apoptosis pathway components and Drp1 contribute to mitotic adaptation.
Conclusions:
- Mitotic arrest involves distinct but interconnected apoptosis and adaptation pathways.
- Crosstalk exists between mitochondrial apoptosis machinery and mitotic adaptation mechanisms.
