Volume 272, Number 47, Issue of November 21, 1997 pp. 29865-29872
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Identification of a Novel Suppressive Vitamin D Response Sequence in the 5-Flanking Region of the Murine Id1 Gene

(Received for publication, February 12, 1997, and in revised form, July 9, 1997)

Yoichi Ezura , Olivia Tournay , Akira Nifuji and Masaki Noda

From the Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101, Japan and the  Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Vitamin D promotes differentiation of cells either by simply enhancing phenotypic gene expression and/or by suppressing expression of inhibitors of differentiation. Previously, we reported that expression of a gene encoding Id1, a negative type helix-loop-helix transcription factor, was transcriptionally suppressed by 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) (1). To identify the sequence required for the negative regulation by 1,25(OH)₂D₃, a 1.5-kilobase 5-flanking region of murine Id1 gene was examined by transiently transfecting luciferase reporter constructs into ROS17/2.8 osteoblastic cells. The transcriptional activity of this construct was repressed by 10⁸ M 1,25(OH)₂D₃. Deletion analysis revealed that a 57-base pair (bp) upstream response sequence (URS) (1146/1090) was required for the suppression by 1,25(OH)₂D₃. This sequence conferred negative responsiveness to 1,25(OH)₂D₃ to a heterologous SV40 promoter. The 57-bp URS contained not only Egr-1 consensus sequence (2) but also four direct repeats of a heptamer sequence (C/A)CAGCCC. Electrophoresis mobility shift assay revealed that the 57-bp URS formed specific nuclear protein-DNA complexes, which were neither competed by previously known positive and negative vitamin D response elements nor supershifted by anti-vitamin D receptor antibody, suggesting the absence of vitamin D receptor in these complexes. These results indicate the involvement of the novel 57-bp sequence in the vitamin D suppression of Id1 gene transcription.

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