c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in response to DNA damage.
The ubiquitously expressed c-Abl tyrosine kinase is activated in the apoptotic response of cells to DNA damage. The mechanisms by which c-Abl signals the induction of apoptosis are not understood. Here we show that c-Abl binds constitutively to the mammalian homolog of the Schizosaccharomyces pombe Rad9 cell cycle checkpoint protein. The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. The results also demonstrate that c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to the antiapototic Bcl-x(L) protein. The regulation of Rad9 by c-Abl in the DNA damage response is further supported by the demonstration that the interaction between c-Abl and Rad9 contributes to DNA damage-induced apoptosis. These findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.
Pubmed ID: 11971963 RIS Download
Apoptosis | Cell Cycle Proteins | Cell Line | DNA Damage | Flow Cytometry | Humans | Phosphorylation | Protein Binding | Proto-Oncogene Proteins c-abl | Proto-Oncogene Proteins c-bcl-2 | Recombinant Fusion Proteins | Transfection | Tyrosine | bcl-X Protein