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c-Myc is necessary for DNA damage-induced apoptosis in the G(2) phase of the cell cycle
1Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA.
Abstract:
The c-myc proto-oncogene encodes a transcription factor that participates in the regulation of cellular proliferation, differentiation, and apoptosis. Ectopic overexpression of c-Myc has been shown to sensitize cells to apoptosis. We report here that cells lacking c-Myc activity due to disruption of the c-myc gene by targeted homologous recombination are defective in DNA damage-initiated apoptosis in the G(2) phase of the cell cycle. The downstream effector of c-Myc is cyclin A, whose ectopic expression in c-myc(-/-) cells rescues the apoptosis defect. The kinetics of the G(2) response indicate that the induction of cyclin A and the concomitant activation of Cdk2 represent an early step during commitment to apoptosis. In contrast, expression of cyclins E and D1 does not rescue the apoptosis defect, and apoptotic processes in G(1) phase are not affected in c-myc(-/-) cells. These observations link DNA damage-induced apoptosis with cell cycle progression and implicate c-Myc in the functioning of a subset of these pathways.
Insights
Cells lacking c-Myc activity are defective in DNA damage-initiated apoptosis. Ectopic expression of cyclin A rescues this defect, linking c-Myc to cell cycle-regulated apoptosis.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The c-myc proto-oncogene encodes a transcription factor regulating cell proliferation, differentiation, and apoptosis.
- Ectopic overexpression of c-Myc sensitizes cells to apoptosis.
Purpose of the Study:
- To investigate the role of c-Myc in DNA damage-induced apoptosis.
- To identify downstream effectors of c-Myc involved in apoptosis regulation.
Main Methods:
- Targeted homologous recombination to disrupt the c-myc gene.
- Analysis of apoptosis in c-myc deficient cells.
- Ectopic expression of cyclins (A, E, D1) to assess rescue of apoptosis defects.
Main Results:
- c-myc(-/-) cells exhibit defective G(2) phase apoptosis following DNA damage.
- Ectopic expression of cyclin A rescues the apoptosis defect in c-myc(-/-) cells.
- Cyclin A induction and Cdk2 activation are early events in apoptosis commitment.
- Cyclins E and D1 do not rescue the defect; G(1) phase apoptosis is unaffected.
Conclusions:
- c-Myc is crucial for DNA damage-induced apoptosis in the G(2) cell cycle phase.
- Cyclin A acts as a downstream effector of c-Myc in this apoptotic pathway.
- c-Myc links DNA damage response, cell cycle progression, and apoptosis.