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Pleiotropic cell-division defects and apoptosis induced by interference with survivin function
F Li1, E J Ackermann, C F Bennett
1Boyer Center for Molecular Medicine, Department of Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
Abstract:
Here we investigate the role of the control of apoptosis in normal cell division. We show that interference with the expression or function of the apoptosis inhibitor survivin causes caspase-dependent cell death in the G2/M phase of the cell cycle, and a cell-division defect characterized by centrosome dysregulation, multipolar mitotic spindles and multinucleated, polyploid cells. Use of a dominant-negative survivin mutant or antisense survivin complementary DNA disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21Waf1/Cip1 within centrosomes, and results in caspase-dependent cleavage of p21. Polyploidy induced by survivin antagonists is accentuated in p21-deficient cells, and corrected by exogenous expression of p21. These findings show that control of apoptosis and preservation of p21 integrity within centrosomes by survivin are required for normal mitotic progression.
Insights
Survivin controls apoptosis and preserves p21 integrity within centrosomes, ensuring normal cell division. Disrupting survivin leads to cell death and defects like polyploidy.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Apoptosis, or programmed cell death, is crucial for normal development and tissue homeostasis.
- Survivin is an apoptosis inhibitor that plays a role in cell division and cancer progression.
Purpose of the Study:
- To investigate the role of survivin in regulating apoptosis during normal cell division.
- To elucidate the molecular mechanisms by which survivin controls mitotic progression and prevents polyploidy.
Main Methods:
- Utilized dominant-negative survivin mutants and antisense survivin complementary DNA to interfere with survivin function.
- Investigated the impact of survivin disruption on cell cycle progression, centrosome integrity, and caspase activity.
- Assessed the role of p21Waf1/Cip1 in survivin-mediated regulation of polyploidy.
Main Results:
- Interference with survivin caused caspase-dependent cell death in the G2/M phase.
- Survivin disruption led to centrosome dysregulation, multipolar spindles, and multinucleated, polyploid cells.
- Survivin antagonists disrupted a centrosomal complex of survivin, caspase-3, and p21Waf1/Cip1, causing p21 cleavage. Polyploidy was exacerbated in p21-deficient cells.
Conclusions:
- Survivin is essential for controlling apoptosis and maintaining p21 integrity within centrosomes.
- Survivin's function is required for normal mitotic progression and prevention of polyploidy.
- Targeting survivin may offer therapeutic strategies for cancer by inducing cell death and mitotic defects.