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J. Biol. Chem., Vol. 278, Issue 51, 51223-51231, December 19, 2003

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Down-regulation of Sp1 Activity through Modulation of O-Glycosylation by Treatment with a Low Glucose Mimetic, 2-Deoxyglucose^*

Hyun Tae Kang, Jung Won Ju, Jin Won Cho¶, and Eun Seong Hwang||

From the Department of Life Science, University of Seoul, Seoul 130-743, Korea and the Department of Biology and Protein Network Research Center, Yonsei University, Seoul 120-749, Korea

2-Deoxyglucose (2-DG), a nonmetabolizable glucose analogue, blocks glycolysis at the phosphohexose isomerase step and has been frequently used as a glucose starvation mimetic in studies of a wide variety of physiological dysfuctions. However, the effect of 2-DG on protein glycosylation and related signal pathways has not been investigated in depth. In HeLa, an HPV18-positive cervical carcinoma line, 2-DG treatment down-regulates human papillomavirus early gene transcription. This down-regulation was also achieved by low glucose supply or hypoxia, suggesting that this is a response commonly modulated by cellular glucose or energy level. We investigated how 2-DG and low glucose affect transcriptional activity. Human papillomavirus gene transcription was only marginally affected by the inhibition of ATP synthesis or the supplementation of pyruvate to 2-DG-treated cells, suggesting that poor ATP generation is involved only to a limited extent. 2-DG treatment also inhibited activation of p21 WAF1 promoter, which is controlled by p53 and/or Sp1. In a reporter assay using p21 WAF1 promoter constructs, 2-DG exerted a strong inhibitory effect on Sp1 activity. DNA binding activity of Sp1 in 2-DG-treated HeLa cells was intact, whereas it was severely impaired in cells incubated in a low glucose medium or in hypoxic condition. Unexpectedly, Sp1 was heavily modified with GlcNAc in 2-DG-treated cells, which is at least partially attributed to the inhibitory effect of 2-DG on N-acetyl--D-glucosaminidase activity. Our results suggest that 2-DG, like low glucose or hypoxic condition, down-regulates Sp1 activity, but through hyper-GlcNAcylation instead of hypo-GlcNAcylation.

Received for publication, July 9, 2003 , and in revised form, September 22, 2003.

^* This work was supported by Grant R11-2002-001-04001-0 from the Korea Science and Engineering Foundation through the Center for Aging and Apoptosis Research at Seoul National University (to H. T. K. and E. S. H.) and by a grant from Protein Network Research Center (Korea Science and Engineering Foundation) (to J. W. J. and J. W. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence may be addressed: Dept. of Biology and Protein Network Research Center, Yonsei University, 134 Sinchondong, Seodaemungu, Seoul 120-749, Korea. E-mail: chojw311{at}yonsei.ac.kr.

^|| To whom correspondence may be addressed: Eun Seong Hwang, 90 Jeonnongdong, Dongdaemungu, Seoul 130-743, Korea. E-mail: eshwang{at}uos.ac.kr.

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