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Computational Analysis of the Caenorhabditis elegans Germline to Study the Distribution of Nuclei, Proteins, and the Cytoskeleton
Published on: April 19, 2018
Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation
Xinzhu Deng1, E Randal Hofmann, Alberto Villanueva
1Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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.
Insights
The Abl-1 protein antagonizes radiation-induced apoptosis in C. elegans germ cells. Inhibiting Abl-1 or its homolog sensitizes cells to DNA damage, suggesting potential cancer drug targets.
Area of Science:
- Cell biology
- Genetics
- Molecular biology
Background:
- c-Abl is a tyrosine kinase involved in genotoxic stress responses, mediating both pro- and antiapoptotic pathways.
- While nuclear c-Abl interacts with p53 homolog p73 to induce apoptosis, cytoplasmic localization is linked to antiapoptotic function, but signals remain unclear.
Purpose of the Study:
- To investigate the role of Abl-1 in DNA damage-induced apoptosis in Caenorhabditis elegans.
- To identify the apoptotic pathway antagonized by Abl-1 and assess the effect of c-Abl inhibitors.
Main Methods:
- Utilized an abl-1 deletion mutant (abl-1(ok171)) in C. elegans to study radiation-induced apoptosis.
- Investigated the genetic requirements of the apoptotic pathway, including cell cycle checkpoint genes and apoptotic machinery components.
- Administered c-Abl inhibitors (STI-571, variants, PD166326) to assess their impact on apoptosis.
Main Results:
- abl-1 deletion mutants exhibited hypersensitivity to radiation-induced apoptosis in the germ line.
- A specific apoptotic pathway antagonized by ABL-1 was delineated, involving clk-2, hus-1, mrt-2, cep-1, ced-3, ced-9, and egl-1.
- ABL-1 did not antagonize apoptosis induced by the DNA-alkylating agent ethylnitrosourea.
- Treatment with c-Abl inhibitors mimicked the phenotype of abl-1 deletion mutants.
Conclusions:
- ABL-1 distinguishes between different types of DNA-damaging signals, specifically antagonizing radiation-induced apoptosis but not that caused by ethylnitrosourea.
- C. elegans serves as a valuable model for studying DNA damage responses and developing novel anticancer drugs targeting c-Abl pathways.
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