title: Role for c-Abl tyrosine kinase in growth arrest response to DNA damage.
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.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Yuan
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: Y
authors.initials: Y
authors.lastname: Whang
authors.forename: C
authors.initials: C
authors.lastname: Sawyers
authors.forename: R
authors.initials: R
authors.lastname: Weichselbaum
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
authors.forename: D
authors.initials: D
authors.lastname: Kufe
mesh_terms: D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000528:radiation effects; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D016315:Proto-Oncogene Proteins c-abl; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases