Caenorhabditis Elegans ABL-1 Antagonizes p53-mediated Germline Apoptosis After Ionizing Irradiation

Nat Genet. 2004 Aug;36(8):906-12. doi: 10.1038/ng1396. Epub 2004 Jul 25.

Abstract

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / radiation effects*
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / radiation effects
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / physiology*
  • Cell Division
  • Cell Line
  • Chromosome Deletion
  • Genes, p53*
  • Models, Genetic
  • Molecular Sequence Data
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / physiology*
  • Transformation, Genetic

Substances

  • Caenorhabditis elegans Proteins
  • ABL-1 protein, C elegans
  • Proto-Oncogene Proteins c-abl