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J. Biol. Chem., Vol. 280, Issue 13, 12503-12516, April 1, 2005

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Elevated 1,4-Galactosyltransferase I in Highly Metastatic Human Lung Cancer Cells

IDENTIFICATION OF E1AF AS IMPORTANT TRANSCRIPTION ACTIVATOR^*

Xiaoyu Zhu, Jianhai Jiang, Hailian Shen, Hanzhou Wang, Hongliang Zong, Zejuan Li, Yanzhong Yang, Ziyue Niu, Weicheng Liu, Xiaoning Chen, Yun Hu¶, and Jianxin Gu¶||

From the State Key Laboratory of Genetic Engineering, Gene Research Center, Shanghai Medical College of Fudan University (former Shanghai Medical University) and the ^¶Department of Molecular Virology, Medical Center of Fudan University (former Shanghai Medical University), Shanghai 200032, People's Republic of China

The elevated levels of 1,4-galactosyltransferase I (GalT I; EC 2.4.1.38) are detected in highly metastatic lung cancer PGBE1 cells compared with its less metastatic partner PGLH7 cells. Decreasing the GalT I surface expression by small interfering RNA or interfering with the surface of GalT I function by mutation inhibited cell adhesion on laminin, the invasive potential in vitro, and tyrosine phosphorylation of focal adhesion kinase. The mechanism by which GalT I activity is up-regulated in highly metastatic cells remains unclear. To investigate the regulation of GalT I expression, we cloned the 5'-region flanking the transcription start point of the GalT I gene (–1653 to +52). Cotransfection of the GalT I promoter/luciferase reporter and the Ets family protein E1AF expression plasmid increased the luciferase reporter activity in a dose-dependent manner. By deletion and mutation analyses, we identified an Ets-binding site between nucleotides –205 and –200 in the GalT I promoter that was critical for responsiveness to E1AF. It was identified that E1AF could bind to and activate the GalT I promoter by electrophoretic mobility shift assay in PGLH7 cells and COS1 cells. A stronger affinity of E1AF for DNA has contributed to the elevated expression of GalT I in PGBE1 cells. Stable transfection of the E1AF expression plasmid resulted in increased GalT I expression in PGLH7 cells, and stable transfectants migrated faster than control cells. Meanwhile, the content of the 1,4-Gal branch on the cell surface was increased in stably transfected PGLH7 cells. GalT I expression can also be induced by epidermal growth factor and dominant active Ras, JNK1, and ERK1. These data suggest an essential role for E1AF in the activation of the human GalT I gene in highly metastatic lung cancer cells.

Received for publication, December 3, 2004

^* This work was supported by 863 Program of China Grant 2001AA234031, National Natural Scientific Foundation of China Grant 30330320, and Mizutani Foundation for Glycoscience of Japan Grant 040025. 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 86-21-54237704; Fax: 86-21-64164489; E-mail: jxgu{at}shmu.edu.cn.

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