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

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.

• Authors: Xinzhu Deng, E Randal Hofmann, Alberto Villanueva, Oliver Hobert, Paola Capodieci, Darren R Veach, Xianglei Yin, Luis Campodonico, Athanasios Glekas, Carlos Cordon-Cardo, Bayard Clarkson, William G Bornmann, Zvi Fuks, Michael O Hengartner, Richard Kolesnick
• Journal: Nature genetics (Nat Genet) Vol. 36 Issue 8 Pg. 906-12 (Aug 2004) ISSN: 1061-4036 [Print] United States
• PMID: 15273685 (Publication Type: Journal Article)

Chemical References

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

Topics

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