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J. Biol. Chem., Vol. 282, Issue 38, 27702-27712, September 21, 2007

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Sequential Action of Ets-1 and Sp1 in the Activation of the Human -1,4-Galactosyltransferase V Gene Involved in Abnormal Glycosylation Characteristic of Cancer Cells^*

From the Laboratory of Glycobiology, Department of Bioengineering, Nagaoka University of Technology, Kamitomioka 1603-1, Nagaoka 940-2188, Japan

Malignant transformation is associated with increased gene expression of -1,4-galactosyltransferase (-1,4-GalT) V, which contributes to the biosynthesis of highly branched N-linked oligosaccharides characteristic of cancer cells. Our previous study showed that expression of the human -1,4-GalT V gene is regulated by Sp1 (Sato, T., and Furukawa, K. (2004) J. Biol. Chem. 279, 39574–39583), and a subsequent study showed that the gene expression is also activated by Ets-1, a product of the oncogene (Sato, T., and Furukawa, K. (2005) Glycoconj. J. 22, 365). Herein we report the mechanism of -1,4-GalT V gene activation by these transcription factors. The gene expression and promoter activity of -1,4-GalT V increased when the ets-1 cDNA was transfected into A549 cells, which contain a small amount of Ets-1, but decreased dramatically when the dominant-negative ets-1 cDNA was transfected into HepG2 cells, which contain a large amount of Ets-1. Luciferase assays using deletion constructs of the -1,4-GalT V gene promoter showed that promoter region –116 to +22 is critical for the transcriptional activation of the gene by Ets-1. Despite the presence of one Ets-1-binding site, which overlapped the Sp1-binding site, electrophoretic mobility shift assays showed that the region bound preferentially to Sp1 rather than to Ets-1. To solve this problem, we examined the transcriptional regulation of the human Sp1 gene by Ets-1 and found that the gene expression and promoter activity of Sp1 are regulated by Ets-1 in cancer cells. Functional analyses of two Ets-1-binding sites in the Sp1 gene promoter showed that only Ets-1-binding site –413 to –404 is involved in the activation of the gene by Ets-1. These results indicate that Ets-1 enhances expression of the -1,4-GalT V gene through activation of the Sp1 gene in cancer cells.

Received for publication, December 28, 2006 , and in revised form, July 24, 2007.

^* This work was supported by Grants-in-aid for the Encouragement of Young Scientists 14771303 and 17790086 (to T. S.) and by Grants-in-aid for Scientific Research 09240104 and 12680708 (to K. F.) from the Ministry of Education, Science, Culture and Sports of Japan. 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.

¹ To whom correspondence should be addressed. Tel.: 81-258-47-9410; Fax: 81-258-47-9400; E-mail: taksato{at}vos.nagaokaut.ac.jp.

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