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Role for c-Abl tyrosine kinase in growth arrest response to DNA damage
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents, and its overexpression causes arrest in the G1 phase of the cell cycle by a mechanism dependent on the tumour-suppressor protein p53 (refs 2-4). Here we investigate the possible role of c-Abl in growth arrest induced by DNA damage. Transient transfection experiments using wild-type or inactivated c-Abl show that both induce expression of p21, an effector of p53, but only wild-type c-Abl downregulates the activity of the cyclin-dependent kinase Cdk2 and causes growth arrest. Exposure to ionizing radiation of cells that stably express active or inactive c-Abl is associated with induction of c-Abl/p53 complexes and p21 expression. However, cells expressing the dominant-negative c-Abl mutant and cells lacking the c-abl gene are impaired in their ability to downregulate Cdk2 or undergo G1 arrest in response to ionizing radiation. We also show that expression of c-Abl kinase in p21(-1-), but not in p53(-1-), cells results in downregulation of Cdk2. Our results suggest that c-Abl kinase contributes to the regulation of growth arrest induced by ionizing radiation by a p53-dependent, p21-independent mechanism.
Insights
The c-Abl protein tyrosine kinase plays a role in DNA damage-induced cell cycle arrest. It regulates Cdk2 activity and G1 arrest via a p53-dependent, p21-independent pathway.
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- DNA Damage Response
Background:
- c-Abl protein tyrosine kinase is activated by DNA damage and linked to G1 cell cycle arrest.
- This arrest is known to be dependent on the tumor suppressor protein p53.
- The precise role of c-Abl in DNA damage-induced growth arrest requires further investigation.
Purpose of the Study:
- To investigate the role of c-Abl in growth arrest induced by DNA damage.
- To elucidate the mechanism by which c-Abl influences cell cycle progression following DNA damage.
- To determine the involvement of p53 and p21 in c-Abl-mediated growth arrest.
Main Methods:
- Transient transfection experiments with wild-type and inactivated c-Abl.
- Analysis of p21 expression and Cdk2 activity.
- Studies on cells stably expressing active or inactive c-Abl after ionizing radiation exposure.
- Experiments using cells lacking the c-abl gene or deficient in p21 or p53.
Main Results:
- Wild-type c-Abl, but not inactivated c-Abl, downregulates Cdk2 activity and induces G1 arrest.
- Ionizing radiation induces c-Abl/p53 complexes and p21 expression in cells expressing active c-Abl.
- Cells with dominant-negative c-Abl or lacking c-abl are impaired in Cdk2 downregulation and G1 arrest after irradiation.
- c-Abl kinase expression downregulates Cdk2 in p21-deficient cells but not in p53-deficient cells.
Conclusions:
- c-Abl kinase is a key regulator of ionizing radiation-induced growth arrest.
- This regulation occurs through a p53-dependent and p21-independent mechanism.
- c-Abl's role extends beyond p53 activation to directly influence Cdk2 activity for cell cycle control.