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Regulation of DNA damage-induced apoptosis by the c-Abl tyrosine kinase
1Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Activation of the c-Abl protein tyrosine kinase by certain DNA-damaging agents contributes to downregulation of Cdk2 and G1 arrest by a p53-dependent mechanism. The present work investigates the potential role of c-Abl in apoptosis induced by DNA damage. Transient transfection studies with wild-type, but not kinase-inactive, c-Abl demonstrate induction of apoptosis. Cells that stably express inactive c-Abl exhibit resistance to ionizing radiation-induced loss of clonogenic survival and apoptosis. Cells null for c-abl are also impaired in the apoptotic response to ionizing radiation. We further show that cells deficient in p53 undergo apoptosis in response to expression of c-Abl and exhibit decreases in radiation-induced apoptosis when expressing inactive c-Abl. These findings suggest that c-Abl kinase regulates DNA damage-induced apoptosis.
Insights
The protein tyrosine kinase c-Abl regulates apoptosis following DNA damage. Active c-Abl induces apoptosis, while its absence confers resistance to DNA damage-induced cell death.
Area of Science:
- Molecular Biology
- Cellular Biology
- Oncology
Background:
- The c-Abl protein tyrosine kinase is activated by DNA-damaging agents.
- c-Abl activation contributes to cell cycle arrest via p53.
- The role of c-Abl in DNA damage-induced apoptosis remains unclear.
Purpose of the Study:
- To investigate the role of c-Abl in apoptosis induced by DNA damage.
- To determine if c-Abl kinase activity is necessary for DNA damage-induced apoptosis.
Main Methods:
- Transient transfection with wild-type and kinase-inactive c-Abl.
- Stable expression of inactive c-Abl in cells.
- Studies using cells null for c-abl.
- Analysis of apoptosis and clonogenic survival following ionizing radiation.
- Experiments involving p53-deficient cells.
Main Results:
- Expression of wild-type c-Abl induces apoptosis.
- Cells expressing inactive c-Abl are resistant to ionizing radiation-induced apoptosis and loss of survival.
- Cells lacking c-Abl show impaired apoptotic responses to ionizing radiation.
- p53-deficient cells undergo apoptosis upon c-Abl expression and show reduced radiation-induced apoptosis when expressing inactive c-Abl.
Conclusions:
- c-Abl kinase activity is crucial for regulating apoptosis in response to DNA damage.
- c-Abl plays a significant role in the cellular response to DNA-damaging agents like ionizing radiation.