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|標題:||Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in A549 adenocarcinoma cells||作者:||Shen, Y.H.
|關鍵字:||hHR23;Cisplatin;Cancer;DNA repair;Cytotoxicity;nucleotide excision-repair;group-c protein;dna-repair;platinum;resistance;p53 degradation;mammalian-cells;human homologs;rad23;xpc;cytotoxicity||Project:||Toxicology Letters||期刊/報告no：:||Toxicology Letters, Volume 205, Issue 3, Page(s) 341-350.||摘要:||
DNA-damaging agents are commonly used as anticancer therapeutics. Unfortunately, such drugs induced DNA damages as well as DNA repair are important in mediating drug resistance to cancer treatments. To evaluate changes in DNA repair proteins that occur in DNA damage agent treatment, we challenged human A549 lung adenocarcinoma cells with cisplatin. hHR23/RAD23, an accessory protein involved in nucleotide-excision repair (NER) at an early lesion-recognition step, was upregulated by cisplatin in a dose- and time-dependent manner. Upregulation of hHR23 expression by low-dose cisplatin was accompanied by an increase in p53, p21, and XPC protein levels. Importantly, knockdown of hHR23B by RNA interference decreased DNA repair activity, cell survival, and induction of p53 and XPC following treatment with cisplatin. Conversely, overexpression of hHR23B enhanced repair activity towards cisplatin-damaged DNA. Inhibition of MEK/ERK and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways attenuated cisplatin-induced hHR23 expression, indicating that these pathways are involved in the process. The increase in hHR23 protein expression mediated by MEK/ERK signaling was due to increased translational efficiency resulting from phosphorylation/activation of the translation-initiating factor eIF-4B. Taken together, these results suggest that cisplatin-induced increases in hHR23 levels are regulated by proliferative signaling pathways and important for DNA repair. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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