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Nat Med. 2009 Oct;15(10):1179-85. doi: 10.1038/nm.2033. Epub 2009 Sep 27.

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

Author information

1
Department of Biology, University of Rome Tor Vergata, Rome, Italy. stefania.gonfloni@uniroma2.it

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.

PMID:
19783996
DOI:
10.1038/nm.2033
[Indexed for MEDLINE]

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