Regulation of cell death by the Abl tyrosine kinase.
The c-abl proto-oncogene encodes a protein tyrosine kinase that is distributed in the nucleus and the cytoplasm of proliferating cells. In the nucleus, c-Abl activity is negatively regulated by the retinoblastoma protein (RB) and positively regulated by DNA damage signals. Activation of the c-Abl kinase by DNA damage requires the function of ATM, which regulates cell cycle checkpoint, DNA repair and apoptosis in response to DNA damage. Cells lacking c-Abl can activate cell cycle checkpoints and DNA repair, but show defects in apoptosis. The apoptosis defect of c-Abl deficient cells is correlated with a defect in the induction and activation of p73, which is a functional homologue of the p53 tumor suppressor protein and has pro-apoptotic activity. The inhibition of c-Abl by RB is consistent with RB's ability to block apoptosis; while the activation of c-Abl by ATM is consistent with ATM's ability to activate cell death. The oncogenic Bcr-Abl tyrosine kinase is a potent inhibitor of apoptosis, and it is retained exclusively in the cytoplasm of transformed cells. Interestingly, when Bcr-Abl is trapped inside of the nucleus through a combined disruption of its cytoplasmic retention and its nuclear export, this oncogenic Abl kinase induces apoptosis. Taken together, the current results support a role for the nuclear c-Abl tyrosine kinase in the regulation of apoptosis. Whether the cytoplasmic c-Abl kinase can actively inhibit apoptosis remains to be determined; however, a deliberate retention of c-Abl in the cytoplasm could potentially contribute to the attenuation of apoptosis response.
Wang
J Y
JY
Department of Biology and the Cancer Center, University of California, San Diego, La Jolla, California, CA 92093-0322, USA.
D017209:Apoptosis / Q000502:physiology*; D004249:DNA Damage; D004789:Enzyme Activation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology
D016160:Retinoblastoma Protein; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl