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首页> 外文期刊>Cell cycle >Modulating c-Abl nuclear activity as a strategy to preserve female fertility.
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Modulating c-Abl nuclear activity as a strategy to preserve female fertility.

机译：调节c-Abl核活性作为维持女性生育力的策略。

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Ovarian failure and infertility are major adverse effects of cancer therapies in children and young women. Studies in mouse models have indicated that TAp63-alpha is expressed in the oocytes of the primordial follicles and required in a process of DNA damage-induced oocyte death following ionizing radiation. However, the upstream events leading to p63 activation via phosphorylation and to cell death are not clarified yet. In addition to ionizing radiation also chemotherapy causes depletion of the follicle reserve. Cisplatin, commonly used in the treatment of a variety of cancers, induces DNA cross-links and is associated with high risk of ovarian failure. This prompted the investigation of the mechanisms underlying the loss of follicular reserve induced by cisplatin with the aim of identifying effective inhibitors that can block the path leading to primordial follicle destruction and thereby reduce ovarian failure. Following cisplatin exposure we observed an accumulation of the p63 and c-Abl protein levels eventually leading to cell death of in vitro cultured ovaries. DNA damage caused by cisplatin has been shown to activate the c-Abl tyrosine kinase. Our studies in model human cell lines revealed that c-Abl phosphorylates p63 on specific tyrosine residues following cisplatin treatment. Tyrosine phosphorylation of Y149 by c-Abl has a marked effect on p63 accumulation and on p63-dependent tran-scriptional activation of the proapoptotic NOXA and PUMA genes. This observation leads us to formulate the hypothesis that pharmacological inhibition of c-Abl may counteract the depletion of the ovarian reserve induced by cisplatin. Notably, treatment with imatinib, an inhibitor of the c-Abl kinase activity, prevents p63 accumulation and eventually oocyte death in cultured ovaries challenged by cisplatin. Intraperitoneal injection of cisplatin in newborn female mice leads to depletion of the follicle reserve and to long term infertility. However, co-injection of imatinib significantly attenuates the toxic effect of cisplatin and partially rescues female mice from cisplatin induced-infertility.
机译：卵巢衰竭和不育症是儿童和年轻女性癌症治疗的主要不良反应。小鼠模型研究表明，TAp63-alpha在原始卵泡的卵母细胞中表达，在电离辐射后DNA损伤诱导的卵母细胞死亡的过程中是必需的。但是，尚不清楚上游事件通过磷酸化导致p63活化并导致细胞死亡。除电离辐射外，化学疗法还会导致卵泡储备的消耗。通常用于治疗多种癌症的顺铂会诱导DNA交联，并与卵巢衰竭的高风险相关。这促使人们研究顺铂诱导的卵泡储备丧失的潜在机制，目的是鉴定有效的抑制剂，这些抑制剂可以阻断导致原始卵泡破坏的途径，从而减少卵巢衰竭。顺铂暴露后，我们观察到p63和c-Abl蛋白水平的积累最终导致体外培养的卵巢细胞死亡。顺铂引起的DNA损伤已显示可激活c-Abl酪氨酸激酶。我们在模型人细胞系中的研究表明，顺铂处理后，c-Abl可使特定酪氨酸残基上的p63磷酸化。 c-Abl对Y149的酪氨酸磷酸化对促凋亡的NOXA和PUMA基因的p63积累和p63依赖性转录激活具有显着影响。该观察结果使我们提出以下假设：药理学抑制c-Abl可抵消顺铂诱导的卵巢储备的消耗。值得注意的是，使用伊马替尼（一种抑制c-Abl激酶活性的抑制剂）进行的治疗可防止p63积聚，并最终阻止顺铂攻击的卵巢中卵母细胞死亡。在新生雌性小鼠中腹膜内注射顺铂会导致卵泡储备的减少和长期不育。然而，伊马替尼的共同注射显着减弱了顺铂的毒性作用，并部分挽救了雌性小鼠免于顺铂引起的不育。

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