Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death
Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death
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DOI：
10.1038/nm.2033
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发表时间：
2009-10-01
期刊：
影响因子：
82.9
通讯作者：
Cesareni, Gianni
中科院分区：
文献类型：
--
作者：
Gonfloni, Stefania;Di Tella, Lucia;Cesareni, Gianni
生殖细胞对基因毒素很敏感，卵巢衰竭和不孕是年轻癌症患者化疗的主要副作用。在这里，我们描述了化疗药物激活的c-Abl-TAp63通路在模型人类细胞系和小鼠卵母细胞中的作用及其在细胞死亡中的作用。在细胞系中，顺铂处理后，c-Abl使TAp63在特定的酪氨酸残基上磷酸化。这些修饰会影响p63的稳定性，并诱导p63依赖的促凋亡启动子的激活。同样，在卵母细胞中，顺铂迅速促进TAp63的积聚，最终导致细胞死亡。用c-Abl激酶抑制剂伊马替尼治疗可抵消顺铂诱导的这些效应。综上所述，这些数据支持一个模型，在该模型中，由DNA双链断裂启动的信号由c-Abl检测，c-Abl通过其激酶活性调节p63的转录输出。此外，他们还提出了伊马替尼的新用途，目的是在化疗期间保存卵泡储备的卵母细胞。
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.