Abstract
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 II (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 (SEΔ) 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 SEΔ. 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.
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Theis, S., Roemer, K. c-Abl tyrosine kinase can mediate tumor cell apoptosis independently of the Rb and p53 tumor suppressors. Oncogene 17, 557–564 (1998). https://doi.org/10.1038/sj.onc.1201973
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DOI: https://doi.org/10.1038/sj.onc.1201973
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