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.
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Xinzhu
X
Deng
E Randal
ER
Hofmann
Alberto
A
Villanueva
Oliver
O
Hobert
Paola
P
Capodieci
Darren R
DR
Veach
Xianglei
X
Yin
Luis
L
Campodonico
Athanasios
A
Glekas
Carlos
C
Cordon-Cardo
Bayard
B
Clarkson
William G
WG
Bornmann
Zvi
Z
Fuks
Michael O
MO
Hengartner
Richard
R
Kolesnick
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000528:radiation effects; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D002872:Chromosome Deletion; D016158:Genes, p53; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014170:Transformation, Genetic
D029742:Caenorhabditis elegans Proteins; C516680:ABL-1 protein, C elegans; D016315:Proto-Oncogene Proteins c-abl