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Volume 272, Number 8, Issue of February 21, 1997 pp. 5024-5030
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Identification of an Insulin-responsive Element in the Rat Insulin-like Growth Factor-binding Protein-3 Gene

(Received for publication, August 5, 1996, and in revised form, October 16, 1996)

Betty C. Villafuerte , Weidong Zhao , Adrian C. Herington ^¶ , Richard Saffery and Lawrence S. Phillips

From the  Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, the ^¶ School of Life Science, Queensland University of Technology, Brisbane, Queensland, Australia 4001, and the  Murdoch Institute, Royal Children's Hospital, Melbourne, Victoria, Australia 3052

The hepatic expression and serum levels of insulin-like growth factor-binding protein-3 (IGFBP-3) are decreased in insulin-dependent and insulin-resistant diabetes. Insulin increases hepatic IGFBP-3 expression by enhancing gene transcription. This report identifies sequences within the IGFBP-3 promoter that are necessary and sufficient for the response to insulin in hepatic nonparenchymal cells. By transient transfection, we mapped the insulin response element to the 1150 to 1124 base pair (bp) region of the rat IGFBP-3 promoter. Three tandem repeats of the 1150 to 1117 bp region conferred insulin responses in a heterologous promoter. Gel shift analyses revealed a 3-fold increase in DNA-protein complex formation with nuclear extracts obtained from insulin-stimulated nonparenchymal cells compared with cells incubated without insulin and revealed 3-4-fold decrease in complex formation with nuclear extracts obtained from the livers of streptozotocin-diabetic rats compared with control rats. Mutational analysis of this 34-bp region showed a core sequence of 10 bp (1148 to 1139) that is critical for interaction with insulin-induced trans-acting factors. Southwestern blotting revealed a ~90-kDa protein that was increased 2-3-fold by the addition of insulin. Thus, we have identified cis-acting DNA sequences that are responsible for regulation of IGFBP-3 transcription by insulin and essential for binding of insulin-responsive nuclear factors.

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