Article abstract
Nature Medicine 15, 1179 - 1185 (2009)
Published online: 27 September 2009 | doi:10.1038/nm.2033
Inhibition of the c-Abl–TAp63 pathway protects mouse oocytes from chemotherapy-induced death
Stefania Gonfloni1, Lucia Di Tella1, Sara Caldarola1, Stefano M Cannata1, Francesca G Klinger2, Claudia Di Bartolomeo1, Maurizio Mattei1, Eleonora Candi3, Massimo De Felici2, Gerry Melino3,4 & Gianni Cesareni1
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.
- Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
- Department of Public Health and Cell Biology, University of Rome 'Tor Vergata', Rome, Italy.
- Department of Experimental Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Medical Research Council, Toxicology Unit, University of Leicester, Leicester, UK.
Correspondence to: Stefania Gonfloni1 e-mail: stefania.gonfloni@uniroma2.it
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