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Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation.

Nature genetics | Aug 30, 2004

http://www.ncbi.nlm.nih.gov/pubmed/15273685

c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function, 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.

Pubmed ID: 15273685 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Apoptosis | Caenorhabditis elegans | Caenorhabditis elegans Proteins | Cell Division | Cell Line | Chromosome Deletion | Genes, p53 | Models, Genetic | Molecular Sequence Data | Proto-Oncogene Proteins c-abl | Transformation, Genetic

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Associated grants

  • Agency: NCI NIH HHS, Id: P01 CA064593
  • Agency: NCI NIH HHS, Id: P30 CA008748

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