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

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.

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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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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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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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