Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Goettingen, Germany.
Exp Dermatol. 2011 Oct;20(10):795-9. doi: 10.1111/j.1600-0625.2011.01320.x. Epub 2011 Jun 24.
Cyclosporin A (CsA) inhibits nucleotide excision repair (NER) in human cells, a process that contributes to the skin cancer proneness in organ transplant patients. We investigated the mechanisms of CsA-induced NER reduction by assessing all xeroderma pigmentosum (XP) genes (XPA-XPG). Western blot analyses revealed that XPA and XPG protein expression was reduced in normal human GM00637 fibroblasts exposed to 0.1 and 0.5 μm CsA. Interestingly, the CsA treatment reduced XPG, but not XPA, mRNA expression. Calcineurin knockdown in GM00637 fibroblasts using RNAi led to similar results suggesting that calcineurin-dependent signalling is involved in XPA and XPG protein regulation. CsA-induced reduction in NER could be complemented by the overexpression of either XPA or XPG protein. Likewise, XPA-deficient fibroblasts with stable overexpression of XPA (XP2OS-pCAH19WS) did not show the inhibitory effect of CsA on NER. In contrast, XPC-deficient fibroblasts overexpressing XPC showed CsA-reduced NER. Our data indicate that the CsA-induced inhibition of NER is a result of downregulation of XPA and XPG protein in a calcineurin-dependent manner.
环孢素 A（CsA）抑制核苷酸切除修复（NER）在人类细胞中，这一过程有助于器官移植患者皮肤癌的易感性。我们通过评估所有着色性干皮病（XP）基因（XPA-XPG）来研究 CsA 诱导的 NER 减少的机制。Western blot 分析显示，暴露于 0.1 和 0.5 μm CsA 的正常人 GM00637 成纤维细胞中 XPA 和 XPG 蛋白表达减少。有趣的是，CsA 处理降低了 XPG，但不降低 XPA 的 mRNA 表达。GM00637 成纤维细胞中钙调神经磷酸酶的 RNAi 敲低导致类似的结果表明钙调神经磷酸酶依赖性信号参与 XPA 和 XPG 蛋白的调节。用 CsA 处理 GM00637 成纤维细胞后，用 XPA 或 XPG 蛋白过表达可部分补偿 NER 的减少。同样，稳定过表达 XPA（XP2OS-pCAH19WS）的 XPA 缺陷型成纤维细胞不会显示 CsA 对 NER 的抑制作用。相反，过表达 XPC 的 XPC 缺陷型成纤维细胞显示出 CsA 降低的 NER。我们的数据表明，CsA 诱导的 NER 抑制是钙调神经磷酸酶依赖性下调 XPA 和 XPG 蛋白的结果。
