Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Genetics volume 36, pages 906–912 (2004)Cite this article

Abstract

c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways1. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis2,3. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function4,5, 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structures of the proteins encoded by wild-type C. elegans abl-1 and the deletion allele abl-1(ok171).
Figure 2: The abl-1(ok171) mutant is hypersensitive to radiation-induced germ-cell apoptosis.
Figure 3: DNA damage checkpoint and p53 mutations prevent germ-cell apoptosis in abl-1(ok171) worms.
Figure 4: Effect of c-Abl tyrosine kinase inhibitors on C. elegans germ-cell apoptosis.
Figure 5: A model for the genetic regulation of the different death programs in C. elegans.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Wang, J.Y. Regulation of cell death by the Abl tyrosine kinase. Oncogene 19, 5643–5650 (2000).

    Article  CAS  Google Scholar 

  2. Gong, J.G. et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806–809 (1999).

    Article  CAS  Google Scholar 

  3. Agami, R., Blandino, G., Oren, M. & Shaul, Y. Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399, 809–813 (1999).

    Article  CAS  Google Scholar 

  4. Vigneri, P. & Wang, J.Y. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat. Med. 7, 228–234 (2001).

    Article  CAS  Google Scholar 

  5. Barila, D. et al. Caspase-dependent cleavage of c-Abl contributes to apoptosis. Mol. Cell. Biol. 23, 2790–2799 (2003).

    Article  CAS  Google Scholar 

  6. Wen, S.T., Jackson, P.K. & Van Etten, R.A. The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. EMBO J. 15, 1583–1595 (1996).

    Article  CAS  Google Scholar 

  7. la Cour, T. et al. NESbase version 1.0: a database of nuclear export signals. Nucleic Acids Res. 31, 393–396 (2003).

    Article  CAS  Google Scholar 

  8. Ellis, R.E., Jacobson, D.M. & Horvitz, H.R. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 129, 79–94 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhou, Z., Caron, E., Hartwieg, E., Hall, A. & Horvitz, H.R. The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev. Cell 1, 477–489 (2001).

    Article  CAS  Google Scholar 

  10. Krause, M., Harrison, S.W., Xu, S.Q., Chen, L. & Fire, A. Elements regulating cell- and stage-specific expression of the C. elegans MyoD family homolog hlh-1. Dev. Biol. 166, 133–148 (1994).

    Article  CAS  Google Scholar 

  11. Hsieh, J. et al. The RING finger/B-box factor TAM-1 and a retinoblastoma-like protein LIN-35 modulate context-dependent gene silencing in Caenorhabditis elegans. Genes Dev. 13, 2958–2970 (1999).

    Article  CAS  Google Scholar 

  12. Hengartner, M.O., Ellis, R.E. & Horvitz, H.R. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356, 494–499 (1992).

    Article  CAS  Google Scholar 

  13. Shaham, S., Reddien, P.W., Davies, B. & Horvitz, H.R. Mutational analysis of the Caenorhabditis elegans cell-death gene ced-3. Genetics 153, 1655–1671 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gartner, A., Milstein, S., Ahmed, S., Hodgkin, J. & Hengartner, M.O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans. Mol. Cell 5, 435–443 (2000).

    Article  CAS  Google Scholar 

  15. Chin, G.M. & Villeneuve, A.M. C. elegans mre-11 is required for meiotic recombination and DNA repair but is dispensable for the meiotic G(2) DNA damage checkpoint. Genes Dev. 15, 522–534 (2001).

    Article  CAS  Google Scholar 

  16. Takanami, T., Mori, A., Takahashi, H. & Higashitani, A. Hyper-resistance of meiotic cells to radiation due to a strong expression of a single recA-like gene in Caenorhabditis elegans. Nucleic Acids Res. 28, 4232–4236 (2000).

    Article  CAS  Google Scholar 

  17. Boulton, S.J. et al. Combined functional genomic maps of the C. elegans DNA damage response. Science 295, 127–131 (2002).

    Article  CAS  Google Scholar 

  18. Rinaldo, C., Bazzicalupo, P., Ederle, S., Hilliard, M. & La Volpe, A. Roles for Caenorhabditis elegans rad-51 in meiosis and in resistance to ionizing radiation during development. Genetics 160, 471–479 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Derry, W.B., Putzke, A.P. & Rothman, J.H. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294, 591–595 (2001).

    Article  CAS  Google Scholar 

  20. Schumacher, B., Hofmann, K., Boulton, S. & Gartner, A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr. Biol. 11, 1722–1727 (2001).

    Article  CAS  Google Scholar 

  21. Kurzrock, R., Gutterman, J.U. & Talpaz, M. The molecular genetics of Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 319, 990–998 (1988).

    Article  CAS  Google Scholar 

  22. Druker, B.J. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol. Med. 8, S14–S18 (2002).

    Article  CAS  Google Scholar 

  23. Nagar, B. et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 62, 4236–4243 (2002).

    CAS  PubMed  Google Scholar 

  24. Gumienny, T.L., Lambie, E., Hartwieg, E., Horvitz, H.R. & Hengartner, M.O. Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126, 1011–1022 (1999).

    CAS  PubMed  Google Scholar 

  25. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    Article  CAS  Google Scholar 

  26. Buchdunger, E. et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 56, 100–104 (1996).

    CAS  PubMed  Google Scholar 

  27. Hamby, J.M. et al. Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J. Med. Chem. 40, 2296–2303 (1997).

    Article  CAS  Google Scholar 

  28. Berman, E. et al. Characterization of two novel sublines established from a human megakaryoblastic leukemia cell line transfected with p210(BCR-ABL). Leuk. Res. 24, 289–297 (2000).

    Article  CAS  Google Scholar 

  29. Wisniewski, D. et al. Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Res. 62, 4244–4255 (2002).

    CAS  PubMed  Google Scholar 

  30. Hofmann, E.R. et al. Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1–mediated apoptosis. Curr. Biol. 12, 1908–1918 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Garriga for the strain gmEx223[pabl-1:GFP], S. Lowe for the retrovirus vectors pLPC and pLPC-h-p53, J. Wang and S. Shaham for critical reading of the manuscript and H. Xing, X. Lin, H, Lee and J. Zhang for technical assistance. This work was supported by grants from the National Institutes of Health to R.K., Z.F., M.O.H., E.R.H. and O.H. and from the Norman and Rosita Winston Foundation to X.D. A.V. is funded by the Spanish Ministry of Science and Technology.

Author information

Author notes

  1. E Randal Hofmann

    Present address: GlaxoSmithKline Comparative Genomics, 1250 South Collegeville Road, UP03/3111D, Collegeville, Pennsylvania, 19426-0989, USA

  2. Alberto Villanueva

    Present address: Laboratory of Translational Research, Institut Català d'Oncologia, 08907 L'Hospitalet de Llobregat, Barcelona, Spain

Authors and Affiliations

  1. Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Xinzhu Deng, Alberto Villanueva, Xianglei Yin, Luis Campodonico & Richard Kolesnick

  2. Department of Molecular Biology, University of Zurich, Winterthurerstrasse 190, Zurich, CH 8057, Switzerland

    E Randal Hofmann & Michael O Hengartner

  3. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, 10032, New York, USA

    Oliver Hobert

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Paola Capodieci & Carlos Cordon-Cardo

  5. Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Darren R Veach, Athanasios Glekas & William G Bornmann

  6. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Bayard Clarkson

  7. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Zvi Fuks

Authors
  1. Xinzhu Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Randal Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Villanueva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oliver Hobert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paola Capodieci
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Darren R Veach
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xianglei Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luis Campodonico
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Athanasios Glekas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carlos Cordon-Cardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bayard Clarkson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. William G Bornmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zvi Fuks
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael O Hengartner
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Richard Kolesnick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard Kolesnick.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

abl-1 encodes five different transcripts generated by cis- and or trans-splicing mechanisms that yield different NH2-termini. (PDF 51 kb)

Supplementary Fig. 2

36 hours post 120 Gy irradiation, germ cell apoptosis in wild-type worms was detected with SYTO as viewed by Nomarski DIC optics and fluorescence imaging. (PDF 361 kb)

Supplementary Fig. 3

The interaction of ABL-1 and human p53 in HEK293 cells after ionizing radiation. (PDF 34 kb)

Supplementary Fig. 4

The schematic diagram of the interaction of PD166326 with the kinase domains of human Abl and C. elegans ABL-1. (PDF 83 kb)

Supplementary Table 1

Germ cell corpses are removed at a normal rate in abl-1(ok171). (PDF 3 kb)

Supplementary Table 2

Programmed cell death genes are required for radiation-induced germ cell apoptosis in abl-1(ok171). (PDF 3 kb)

Supplementary Methods (PDF 29 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deng, X., Hofmann, E., Villanueva, A. et al. Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation. Nat Genet 36, 906–912 (2004). https://doi.org/10.1038/ng1396

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1396

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing