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

Stefania Gonfloni, Lucia Di Tella, Sara Caldarola, Stefano M. Cannata, Francesca G. Klinger, Claudia Di Bartolomeo, Maurizio Mattei, Eleonora Candi, Massimo De Felici, Gerry Melino, Gianni Cesareni

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1179-1185
Number of pages7
JournalNature Medicine
Volume15
Issue number10
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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