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

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

Authors

  • Deng X
  • Hofmann ER
  • Villanueva A
  • Hobert O
  • Capodieci P
  • Veach DR
  • Yin X
  • Campodonico L
  • Glekas A
  • Cordon-Cardo C
  • Clarkson B
  • Bornmann WG
  • Fuks Z
  • Hengartner MO
  • Kolesnick R

Journal

Nature genetics

Publication Data

August 30, 2004

Associated Grants

None

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