Journal
EXPERIMENTAL DERMATOLOGY
Volume 20, Issue 10, Pages 795-799Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1600-0625.2011.01320.x
Keywords
calcineurin; cyclosporin A; nucleotide excision repair; UV-induced skin cancer; xeroderma pigmentosum
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Funding
- Deutsche Forschungsgemeinschaft [GRK 1034]
- Deutsche Krebshilfe
- Niedersachsische Krebsgesellschaft
- Faculty of Medicine, Georg-August-University of Goettingen
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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 mu m 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.
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