Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death.
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.
Gonfloni
Stefania
S
Department of Biology, University of Rome Tor Vergata, Rome, Italy. stefania.gonfloni@uniroma2.it
Di Tella
Lucia
L
Caldarola
Sara
S
Cannata
Stefano M
SM
Klinger
Francesca G
FG
Di Bartolomeo
Claudia
C
Mattei
Maurizio
M
Candi
Eleonora
E
De Felici
Massimo
M
Melino
Gerry
G
Cesareni
Gianni
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D016313:Genes, abl / Q000187:drug effects*; D000068877:Imatinib Mesylate; D020287:In Situ Nick-End Labeling; D051379:Mice; D009865:Oocytes / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors*
D001549:Benzamides; D003432:Cross-Linking Reagents; D010750:Phosphoproteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D000068877:Imatinib Mesylate; D002945:Cisplatin