Nature Genetics
36, 906 - 912 (2004)
Published online: 25 July 2004; | doi:10.1038/ng1396
Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiationXinzhu Deng1, E Randal Hofmann2, 8, Alberto Villanueva1, 8, Oliver Hobert3, Paola Capodieci4, Darren R Veach5, Xianglei Yin1, Luis Campodonico1, Athanasios Glekas5, Carlos Cordon-Cardo4, Bayard Clarkson6, William G Bornmann5, Zvi Fuks7, Michael O Hengartner2
& Richard Kolesnick11
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. 2
Department of Molecular Biology, University of Zurich, Winterthurerstrasse 190 CH 8057, Zurich, Switzerland. 3
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. 4
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. 5
Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. 6
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. 7
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. 8
Present addresses: GlaxoSmithKline Comparative Genomics, 1250 South Collegeville Road, UP03/3111D Collegeville, Pennsylvania 19426-0989, USA (R.H.); Laboratory of Translational Research, Institut Català d'Oncologia, 08907 L'Hospitalet de Llobregat, Barcelona, Spain (A.V.).
Correspondence should be addressed to Richard Kolesnick r-kolesnick@ski.mskcc.orgc-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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