c-Abl tyrosine kinase can mediate tumor cell apoptosis independently of the Rb and p53 tumor suppressors.
Tumor cells frequently lack the p53 tumor suppressor because p53 mediates apoptosis in these cells. We report here that c-Abl, and to a greater extent a c-Abl mutant defective for DNA-binding, can provoke programmed cell death in p53-deficient tumor cells. Tyrosine kinase mutant K290R is less cytotoxic. In contrast, a C-terminal deletion mutant that lacks the RNA polymerase 11 (PolII)/actin interaction domain, fails to mediate apoptosis unless expressed to very high levels. Cytotoxicity is overcome by coexpression of the apoptosis antagonist E1B 19K protein, and partially overcome by full-length retinoblastoma protein (Rb) or the C pocket fragment of Rb (SEA) that associates with c-Abl. c-Abl is also highly toxic to Saos-2 cells that are deficient for both Rb and p53, indicating that cell death is not the result of inhibition through c-Abl of the anti-apoptotic function of Rb. Finally, p53 and c-Abl combined induce apoptosis stronger than either protein alone. Unlike c-Abl-mediated cell death, apoptosis by p53 is antagonized efficiently only by full-length Rb with intact A/B pocket but not by SEA. Mutant p53 inhibits apoptosis by p53 but not c-Abl. Thus, c-Abl with intact kinase and PolII/ actin-binding domains can affect tumor cell survival independently of Rb and p53.
Department of Virology, University of Saarland Medical School, Homburg/Saar, Germany.
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D000199:Actins / Q000378:metabolism; D017209:Apoptosis; D001120:Arginine / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002470:Cell Survival; D016147:Genes, Tumor Suppressor; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D016315:Proto-Oncogene Proteins c-abl; D012319:RNA Polymerase II; D008239:Lysine