Abstract
c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways1. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis2,3. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function4,5, the signals that mediate its antiapoptotic effect are largely unknown. Here we show that worms carrying an abl-1 deletion allele, abl-1(ok171), are specifically hypersensitive to radiation-induced apoptosis in the Caenorhabditis elegans germ line. Our findings delineate an apoptotic pathway antagonized by ABL-1, which requires sequentially the cell cycle checkpoint genes clk-2, hus-1 and mrt-2; the C. elegans p53 homolog, cep-1; and the genes encoding the components of the conserved apoptotic machinery, ced-3, ced-9 and egl-1. ABL-1 does not antagonize germline apoptosis induced by the DNA-alkylating agent ethylnitrosourea. Furthermore, worms treated with the c-Abl inhibitor STI-571 (Gleevec; used in human cancer therapy), two newly synthesized STI-571 variants or PD166326 had a phenotype similar to that generated by abl-1(ok171). These studies indicate that ABL-1 distinguishes proapoptotic signals triggered by two different DNA-damaging agents and suggest that C. elegans might provide tissue models for development of anticancer drugs.
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Acknowledgements
We thank G. Garriga for the strain gmEx223[pabl-1:GFP], S. Lowe for the retrovirus vectors pLPC and pLPC-h-p53, J. Wang and S. Shaham for critical reading of the manuscript and H. Xing, X. Lin, H, Lee and J. Zhang for technical assistance. This work was supported by grants from the National Institutes of Health to R.K., Z.F., M.O.H., E.R.H. and O.H. and from the Norman and Rosita Winston Foundation to X.D. A.V. is funded by the Spanish Ministry of Science and Technology.
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Supplementary information
Supplementary Fig. 1
abl-1 encodes five different transcripts generated by cis- and or trans-splicing mechanisms that yield different NH2-termini. (PDF 51 kb)
Supplementary Fig. 2
36 hours post 120 Gy irradiation, germ cell apoptosis in wild-type worms was detected with SYTO as viewed by Nomarski DIC optics and fluorescence imaging. (PDF 361 kb)
Supplementary Fig. 3
The interaction of ABL-1 and human p53 in HEK293 cells after ionizing radiation. (PDF 34 kb)
Supplementary Fig. 4
The schematic diagram of the interaction of PD166326 with the kinase domains of human Abl and C. elegans ABL-1. (PDF 83 kb)
Supplementary Table 1
Germ cell corpses are removed at a normal rate in abl-1(ok171). (PDF 3 kb)
Supplementary Table 2
Programmed cell death genes are required for radiation-induced germ cell apoptosis in abl-1(ok171). (PDF 3 kb)
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Deng, X., Hofmann, E., Villanueva, A. et al. Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation. Nat Genet 36, 906–912 (2004). https://doi.org/10.1038/ng1396
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DOI: https://doi.org/10.1038/ng1396
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