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Inhibition of the c-Abl–TAp63 pathway protects mouse oocytes from chemotherapy-induced death

Nature Medicine volume 15, pages 1179–1185 (2009)Cite this article

Abstract

Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl–TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. Similarly, in oocytes, cisplatin rapidly promotes TAp63 accumulation and eventually cell death. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Taken together, these data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl, which, through its kinase activity, modulates the p63 transcriptional output. Moreover, they suggest a new use for imatinib, aimed at preserving oocytes of the follicle reserve during chemotherapeutic treatments.

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Figure 1: Cisplatin treatment induces accumulation of TAp63 and death in early postnatal oocytes.
Figure 2: Cisplatin directly affects p63 transcriptional activity.
Figure 3: Cisplatin induces c-Abl nuclear accumulation and cleavage.
Figure 4: Active c-Abl mutant phosphorylates and stabilizes TAp63-α.
Figure 5: Cisplatin treatment induces a massive depletion of follicle reserve.
Figure 6: Imatinib treatment prolongs the reproductive outcome after cisplatin treatment.

References

  1. Kastan, M.B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    Article  CAS  Google Scholar 

  2. Zhou, B.B. & Elledge, S.J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000).

    Article  CAS  Google Scholar 

  3. Harris, S.L. & Levine, A.J. The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899–2908 (2005).

    Article  CAS  Google Scholar 

  4. De Felici, M. et al. Experimental approaches to the study of primordial germ cell lineage and proliferation. Hum. Reprod. Update 10, 197–206 (2004).

    Article  CAS  Google Scholar 

  5. Suh, E.K. et al. p63 protects the female germ line during meiotic arrest. Nature 444, 624–628 (2006).

    Article  CAS  Google Scholar 

  6. Livera, G. et al. p63 null mutation protects mouse oocytes from radio-induced apoptosis. Reproduction 135, 3–12 (2008).

    Article  CAS  Google Scholar 

  7. Yang, A., Kaghad, M., Caput, D. & McKeon, F. On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet. 18, 90–95 (2002).

    Article  Google Scholar 

  8. Yang, A. et al. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2, 305–316 (1998).

    Article  CAS  Google Scholar 

  9. Katoh, M.A. et al. Female-specific dominant lethal effects in mice. Mutat. Res. 230, 205–217 (1990).

    Article  CAS  Google Scholar 

  10. Blommaert, F.A. & Saris, C.P. Detection of platinum-DNA adducts by 32P-postlabelling. Nucleic Acids Res. 23, 1300–1306 (1995).

    Article  CAS  Google Scholar 

  11. 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 

  12. Liu, Z.G. et al. Three distinct signalling responses by murine fibroblasts to genotoxic stress. Nature 384, 273–276 (1996).

    Article  CAS  Google Scholar 

  13. Kharbanda, S. et al. c-Abl activation regulates induction of the SEK1/stress-activated protein kinase pathway in the cellular response to 1-β-D-arabinofuranosylcytosine. J. Biol. Chem. 270, 30278–30281 (1995).

    Article  CAS  Google Scholar 

  14. Kharbanda, S. et al. Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage. Mol. Cell. Biol. 20, 4979–4989 (2000).

    Article  CAS  Google Scholar 

  15. Pandey, P. et al. Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and -independent mechanisms. J. Biol. Chem. 271, 23775–23779 (1996).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  17. Machuy, N., Rajalingam, K. & Rudel, T. Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis. Cell Death Differ. 11, 290–300 (2004).

    Article  CAS  Google Scholar 

  18. Agami, R., Blandino, G., Oren, M. & Shaul, Y. Interaction of c-Abl and p73α and their collaboration to induce apoptosis. Nature 399, 809–813 (1999).

    Article  CAS  Google Scholar 

  19. Kharbanda, S., Yuan, Z.M., Weichselbaum, R. & Kufe, D. Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 17, 3309–3318 (1998).

    Article  Google Scholar 

  20. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  Google Scholar 

  21. Melino, G. et al. Functional regulation of p73 and p63: development and cancer. Trends Biochem. Sci. 28, 663–670 (2003).

    Article  CAS  Google Scholar 

  22. Tsai, K.K. & Yuan, Z.M. c-Abl stabilizes p73 by a phosphorylation-augmented interaction. Cancer Res. 63, 3418–3424 (2003).

    CAS  PubMed  Google Scholar 

  23. Goldberg, Z. et al. Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation. EMBO J. 21, 3715–3727 (2002).

    Article  CAS  Google Scholar 

  24. Mantovani, F. et al. Pin1 links the activities of c-Abl and p300 in regulating p73 function. Mol. Cell 14, 625–636 (2004).

    Article  CAS  Google Scholar 

  25. Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol. Cell 18, 447–459 (2005).

    Article  CAS  Google Scholar 

  26. Levy, D., Adamovich, Y., Reuven, N. & Shaul, Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol. Cell 29, 350–361 (2008).

    Article  CAS  Google Scholar 

  27. Yuan, Z.M. et al. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399, 814–817 (1999).

    Article  CAS  Google Scholar 

  28. Sanchez-Prieto, R., Sanchez-Arevalo, V.J., Servitja, J.M. & Gutkind, J.S. Regulation of p73 by c-Abl through the p38 MAP kinase pathway. Oncogene 21, 974–979 (2002).

    Article  CAS  Google Scholar 

  29. Rossi, M. et al. The ubiquitin-protein ligase Itch regulates p73 stability. EMBO J. 24, 836–848 (2005).

    Article  CAS  Google Scholar 

  30. Melino, G., Knight, R.A. & Cesareni, G. Degradation of p63 by Itch. Cell Cycle 5, 1735–1739 (2006).

    Article  CAS  Google Scholar 

  31. Yoshida, K. et al. JNK phosphorylation of 14–3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat. Cell Biol. 7, 278–285 (2005).

    Article  CAS  Google Scholar 

  32. Raina, D. et al. MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. EMBO J. 25, 3774–3783 (2006).

    Article  CAS  Google Scholar 

  33. Chen, Z. et al. ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene 18, 173–180 (1999).

    Article  CAS  Google Scholar 

  34. Jones, E.V., Dickman, M.J. & Whitmarsh, A.J. Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase. Biochem. J. 405, 617–623 (2007).

    Article  CAS  Google Scholar 

  35. Barilà, D. et al. A nuclear tyrosine phosphorylation circuit: c-Jun as an activator and substrate of c-Abl and JNK. EMBO J. 19, 273–281 (2000).

    Article  Google Scholar 

Download references

Acknowledgements

We thank G. Mazzeo for critical suggestions and support. We thank G. Superti-Furga for critical reading of the manuscript. We thank R. Sacco for help in preparing some figures. We thank S. Bernardini, M. Angelini, A.M. Lena, A. Gamboi-Miraglia, M. Ranalli and G. Palmieri for technical advice. This work was supported by Associazione Italiana per la Ricerca sul Cancro to S.G. and G.C., and the EU integrated projects Interaction Proteome to G.C. and EPISTEM to G.M.

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Authors and Affiliations

  1. Department of Biology, University of Rome 'Tor Vergata', Rome, Italy

    Stefania Gonfloni, Lucia Di Tella, Sara Caldarola, Stefano M Cannata, Claudia Di Bartolomeo, Maurizio Mattei & Gianni Cesareni

  2. Department of Public Health and Cell Biology, University of Rome 'Tor Vergata', Rome, Italy

    Francesca G Klinger & Massimo De Felici

  3. Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy

    Eleonora Candi & Gerry Melino

  4. Medical Research Council, Toxicology Unit, University of Leicester, Leicester, UK

    Gerry Melino

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  1. Stefania Gonfloni
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Contributions

S.G. designed, performed and analyzed the majority of the experiments and wrote the paper. L.D.T. helped with experiments in cells. S.C. did quantitative RT-PCR experiments. S.M.C. performed BrdU labeling experiments. F.G.K. did ovary culturing and TUNEL staining. C.D.B. collected adult ovaries. M.M. did mouse injections. E.C. provided support and the SaosTAp63 cell line. M.D.F. provided a key contribution for the project and edited the manuscript. G.M. provided a key contribution for the development of project and pointed out the in vivo strategy. G.C. supervised the project and wrote most of the manuscript.

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Correspondence to Stefania Gonfloni.

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Competing interests

S.G. and G.C. submitted a patent for the use of c-Abl inhibitors to protect oocytes from the toxic effects induced by chemotherapy to the Italian Patent Office, with patent number RM2008A000684 on 19 December 2008.

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Supplementary Figs. 1–5 and Supplementary Methods (PDF 457 kb)

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Gonfloni, S., Di Tella, L., Caldarola, S. et al. Inhibition of the c-Abl–TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat Med 15, 1179–1185 (2009). https://doi.org/10.1038/nm.2033

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