Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death - PubMed (original) (raw)

. 2009 Oct;15(10):1179-85.

doi: 10.1038/nm.2033. Epub 2009 Sep 27.

Affiliations

• PMID: 19783996
• DOI: 10.1038/nm.2033

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

Stefania Gonfloni et al. Nat Med. 2009 Oct.

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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Comment in

• Preserving fertility during cancer treatment.
  Woodruff TK. Woodruff TK. Nat Med. 2009 Oct;15(10):1124-5. doi: 10.1038/nm1009-1124. Nat Med. 2009. PMID: 19812566 Free PMC article.
• Cisplatin-induced primordial follicle oocyte killing and loss of fertility are not prevented by imatinib.
  Kerr JB, Hutt KJ, Cook M, Speed TP, Strasser A, Findlay JK, Scott CL. Kerr JB, et al. Nat Med. 2012 Aug;18(8):1170-2; author reply 1172-4. doi: 10.1038/nm.2889. Nat Med. 2012. PMID: 22869179 Free PMC article. No abstract available.

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