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Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin
D S O'Connor1, D Grossman, J Plescia
1Departments of Pathology, Dermatology, and Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Abstract:
The interface between apoptosis (programmed cell death) and the cell cycle is essential to preserve homeostasis and genomic integrity. Here, we show that survivin, an inhibitor of apoptosis over-expressed in cancer, physically associates with the cyclin-dependent kinase p34(cdc2) on the mitotic apparatus, and is phosphorylated on Thr(34) by p34(cdc2)-cyclin B1, in vitro and in vivo. Loss of phosphorylation on Thr(34) resulted in dissociation of a survivin-caspase-9 complex on the mitotic apparatus, and caspase-9-dependent apoptosis of cells traversing mitosis. These data identify survivin as a mitotic substrate of p34(cdc2)-cyclin B1 and suggest that survivin phosphorylation on Thr(34) may be required to preserve cell viability at cell division. Manipulation of this pathway may facilitate the elimination of cancer cells at mitosis.
Insights
Survivin, an apoptosis inhibitor, is phosphorylated by p34(cdc2)-cyclin B1 during mitosis. This phosphorylation is crucial for preventing cell death, offering a potential strategy to eliminate cancer cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Apoptosis and cell cycle regulation are vital for maintaining cellular homeostasis and genomic stability.
- Survivin, an inhibitor of apoptosis, is frequently overexpressed in various cancers.
Purpose of the Study:
- To investigate the interaction between survivin and the cell cycle machinery.
- To elucidate the role of survivin phosphorylation in regulating apoptosis during mitosis.
Main Methods:
- Co-immunoprecipitation assays to detect protein-protein interactions.
- In vitro and in vivo phosphorylation studies using survivin and p34(cdc2)-cyclin B1.
- Analysis of apoptosis induction upon loss of survivin phosphorylation.
Main Results:
- Survivin physically associates with p34(cdc2) on the mitotic apparatus.
- Survivin is phosphorylated on Thr(34) by p34(cdc2)-cyclin B1.
- Loss of Thr(34) phosphorylation leads to survivin-caspase-9 complex dissociation and caspase-9-dependent apoptosis during mitosis.
Conclusions:
- Survivin acts as a mitotic substrate for p34(cdc2)-cyclin B1.
- Phosphorylation of survivin at Thr(34) is essential for maintaining cell viability during cell division.
- Targeting this survivin phosphorylation pathway could be a therapeutic approach for eliminating cancer cells during mitosis.