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J. Biol. Chem., Vol. 278, Issue 38, 36611-36620, September 19, 2003

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Lewis Type 1 Antigen Synthase (3Gal-T5) Is Transcriptionally Regulated by Homeoproteins^*

Soichiro Isshiki  , Takashi Kudo  ¶ ||, Shoko Nishihara , Yuzuru Ikehara  **, Akira Togayachi  ¶ ||, Akiko Furuya , Kenya Shitara , Tetsuro Kubota , Masahiko Watanabe , Masaki Kitajima  and Hisashi Narimatsu  ¶ 

From the Division of Cell Biology, Institute of Life Science, Soka University, Tangi-cho, Hachioji, Tokyo 192-8577, ^¶Glycogene Function Team, Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Open Space Laboratory Central 2, 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Department of Surgery, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, ^**Division of Oncological Pathology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464-0021, and Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan

The type 1 carbohydrate chain, Gal1–3GlcNAc, is synthesized by UDP-galactose:-N-acetylglucosamine 1,3-galactosyltransferase (3Gal-T). Among six 3Gal-Ts cloned to date, 3Gal-T5 is an essential enzyme for the synthesis of type 1 chain in epithelium of digestive tracts or pancreatic tissue. It forms the type 1 structure on glycoproteins produced from such tissues. In the present study, we found that the transcriptional regulation of the 3Gal-T5 gene is controlled by homeoproteins, i.e. members of caudal-related homeobox protein (Cdx) and hepatocyte nuclear factor (HNF) families. We found an important region (–151 to –121 from the transcription initiation site), named the 3Gal-T5 control element (GCE), for the promoter activity. GCE contained the consensus sequences for members of the Cdx and HNF families. Mutations introduced into this sequence abolished the transcriptional activity. Four factors, Cdx1, Cdx2, HNF1, and HNF1, could bind to GCE and transcriptionally activate the 3Gal-T5 gene. Transcriptional regulation of the 3Gal-T5 gene was consistent with that of members of the Cdx and HNF1 families in two in vivo systems. 1) During in vitro differentiation of Caco-2 cells, transcriptional up-regulation of 3Gal-T5 was observed in correlation with the increase in transcripts for Cdx2 and HNF1. 2) Both transcript and protein levels of 3Gal-T5 were determined to be significantly reduced in colon cancer. This down-regulation was correlated with the decrease of Cdx1 and HNF1 expression in cancer tissue. This is the first finding that a glycosyltransferase gene is transcriptionally regulated under the control of homeoproteins in a tissue-specific manner. 3Gal-T5, controlled by the intestinal homeoproteins, may play an important role in the specific function of intestinal cells by modifying the carbohydrate structure of glycoproteins.

Received for publication, March 17, 2003 , and in revised form, June 27, 2003.

^* 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.

^|| Present address: Glycogene Function Team, Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Open Space Laboratory Central 2, 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568, Japan.

To whom correspondence should be addressed: Glycogene Function Team, Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology, Open Space Laboratory Central-2, 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan. Tel.: 81-298-61-3200; Fax: 81-298-61-3201; E-mail: h.narimatsu{at}aist.go.jp.

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