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J. Biol. Chem., Vol. 276, Issue 4, 2440-2450, January 26, 2001

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Acceleration of Thrombomodulin Gene Transcription by Retinoic Acid
RETINOIC ACID RECEPTORS AND Sp1 REGULATE THE PROMOTER ACTIVITY THROUGH INTERACTIONS WITH TWO DIFFERENT SEQUENCES IN THE 5'-FLANKING REGION OF HUMAN GENE^*

Shuichi Horie, Hidemi Ishii^§, Fumiko Matsumoto, Masao Kusano, Keiichiro Kizaki, Juzo Matsuda, and Mutsuyoshi Kazama

From the Department of Clinical Biochemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Tsukui, Kanagawa 199-0195 and the ^§ Department of Public Health, Showa College of Pharmaceutical Sciences, Higashi Tamagawagakuen, Machida, Tokyo 194-8543, Japan

The interactions between retinoic acid- (RA)-dependent transcriptional regulatory sequences of the 5'-untranslated region of the thrombomodulin gene and nuclear RA-responsive proteins were studied using human pancreas BxPC-3 cells. Deletion mutants of pTM-CAT plasmid revealed the presence of distal and proximal RA-responsive regions containing direct repeat with 4 spaces (DR4) and three of four Sp1 sites, respectively. Cotransfection of a pTM-CAT plasmid with expression plasmids of RA receptors (RAR, RAR, and RAR) augmented the promoter activity under the condition of lower retinoid X receptor- (RXR) expression, whereas the activity was greatly diminished when RXR was highly expressed. An electrophoretic mobility shift assay with cDNA containing the DR4 indicated that heterodimers of RAR and RXR interacted with the DR4 site, although the interaction gradually disappeared with the increase in the ratio of RXR/RAR. On the other hand, Sp1 protein interacted especially with the tandem Sp1 site corresponding to the first and second Sp1 sequences of the four Sp1 sites in the proximal RA-responsive region. The binding of Sp1 to Sp1 sites was independent of RAR-RXR heterodimer but increased with the increase in Sp1 concentration in the presence of unknown factor(s) of reticulocyte lysate. Upon treatment of the cells with RA, time-dependent increases in the ratio of RAR to RXR and the phosphorylated form of Sp1 were observed. We concluded that two genomic DNA regions, the DR4 site (1531 to 1516) and the first and second Sp1-binding sites (145 to 121), were involved in the RA-dependent augmentation of thrombomodulin gene expression through increased interactions of the two regions with heterodimer of RAR-RXR and nuclear Sp1, respectively.

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