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KMID : 0385220030130010039
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Korean Journal of Gerontology
2003 Volume.13 No. 1 p.39 ~ p.45
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2-Deoxyglucose, a low glucose mimetic, downregulates HPV E6/E7 genes through modulation of glycosylation level of transcription factors in cervical cancer cells
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Kang Hyun-Tae
Hwang Eun-Seong
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Abstract
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-deoxyglucose (2-DG), a non-metabolizable glucose analogue, blocks glycolysis at phosphohexose isomerase step, and has been frequently used as a means of calorie restriction mimetic and a method for glucose-starvation mimetic in studies of a wide variety of physiological dysfunctions. Despite extensive utilization, however, the effect of 2-DG on protein glycosylation and related signal pathway has not been closely investigated, nor significantly considered. In HeLa, an HPV-positive cervical carcinoma cell line whose proliferation is dependent on HPV oncogene expression, 2-DG treatment was shown to downregulate HPV transcription. In this study, the underlying mechanisms for the down-regulation in E6/E7 expression were investigated. Treatment of an inhibitor for ATP synthesis caused a marginal decrease in E6/E7 gene expression, suggesting that poor ATP generation may be involved in the down-regulation of HPV early genes expression, but to a limited extent. Treatment of cells with tunicamycin that blocks N-linked glycosylation of proteins had a minimal effect, suggesting that poor N-linked glycosylation is not involved, either. In addition to HPV genes, p21WAF1 transcription was also downregulated by the treatment of 2-DG, suggesting an involvement of a transcription activator such as Sp1 that functions in both genes. We also found that O-linked Nacetylglucosaminylation of Sp1 was changed significantly in the 2-DG treated cells. From these results, we propose that the altered O-linked glycosylation causes a decrease in Sp1 transcriptional activity, this in turn causes downregulation of HPV early gene expression in cells fed with 2-DG. Therefore, 2-DG not only induces a cellular state similar to glucose starvation, but also causes alteration in the activity of key transcription factors.
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KEYWORD
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cervical cancer, 2-deoxyglucose, human papillomavirus E6/E7, O-GlcNAc, glucose starvation, Sp1
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