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

Authors: Deng, X.; Hofmann, E. R.; Villanueva, A.; Hobert, O.; Capodieci, P.; Veach, D. R.; Yin, X.; Campodonico, L.; Glekas, A.; Cordon-Cardo, C.; Clarkson, B.; Bornmann, W. G.; Fuks, Z.; Hengartner, M. O.; Kolesnick, R.
Article Title: 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.
Keywords: unclassified drug; gene deletion; nonhuman; protein localization; animals; gene; cell cycle; cell division; imatinib; apoptosis; protein protein interaction; cell line; gene product; gene function; enzyme inhibitor; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; abelson kinase; protein p53; germ line; amino acid sequence; molecular sequence data; nucleotide sequence; tyrosine kinase receptor; ionizing radiation; cellular distribution; cytoplasm; radiosensitivity; models, genetic; caenorhabditis elegans; worm; sequence homology; chromosome deletion; genes, p53; protein p73; transformation, genetic; caenorhabditis; proto-oncogene proteins c-abl; allelism; abelson kinase inhibitor; priority journal; article; gene abl 1; gene ced 3; gene ced 9; gene cep 1; gene clk 2; gene egl 1; gene hus 1; gene mrt 2
Journal Title: Nature Genetics
Volume: 36
Issue: 8
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2004-08-01
Start Page: 906
End Page: 912
Language: English
DOI: 10.1038/ng1396
PROVIDER: scopus
PUBMED: 15273685
Notes: Nat. Genet. -- Cited By (since 1996):46 -- Export Date: 16 June 2014 -- CODEN: NGENE -- Molecular Sequence Numbers: GENBANK: NM_005157, NM_077376, NM_077377, Z50806; -- Source: Scopus
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