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  • Title: Multiple liver-enriched trans-acting factors interact with the glucocorticoid- (GRU) and cAMP-(CRU) responsive units within the h-IGFBP-1 promoter.
    Author: Neau E, Chambéry D, Schweizer-Groyer G, Cadepond F, Jibard N, Groyer A.
    Journal: Prog Growth Factor Res; 1995; 6(2-4):103-17. PubMed ID: 8817652.
    Abstract:
    In response to hormonal control, serum concentrations of insulin-like growth factor-binding protein-1 (IGFBP-1) may vary as much as 10-fold, owing to strict control of its gene's expression in hepatocytes. IGFBP-1 gene transcription is increased by glucocorticoids and cAMP and inhibited by insulin. The effect of insulin is dominant since it suppresses constitutive and both glucocorticoid- and cAMP-stimulated transcription. Close examination of the human (h)IGFBP-1 promoter sequences showed that the glucocorticoid (GRE, nt -88 to -102) and cAMP (CRE, nt -259 to -264) response elements are 5'-flanked by an A/T-rich imperfect palindrome (nt -102 to -117 and -265 to -285, respectively). These A/T-rich motifs are putative cis-elements for liver-enriched trans-acting factors. Competition experiments in electrophoretic mobility shift assay were carried out using rat liver nuclear extracts and a set of synthetic oligonucleotides designed from hIGFBP-1 Glucorticoid and cAMP Response Units (GRU and CRU), the rat transthyretin HNF3 cis-element and the "D-site' of the mouse albumin promoter. The nucleotide motifs located between nt -108 and -121 of the GRU, interacted with the HNF3 family of trans-acting factors (alpha, beta, gamma), whereas those encompassing nt -81 to -104 bound DBP and/or nuclear proteins sharing similar sequence specificity (i.e. from the C/EBP family of bZIP proteins). We have also shown that the hIGFBP-1-GRE binds glucocorticoid receptor homodimers. In the case of the CRU, the cis-elements located between nt -249 and -285 bound DBP and/or nuclear proteins sharing similar sequence specificities. In addition, the nucleotide stretch lying between nt -256 and -275 was able to interact with the HNF3 family of trans-acting factors. Our results support the view that the dominant inhibitory effect of insulin over glucocorticoid- and cAMP- enhanced transcription may be mediated by different target sequences located 5'- of the GRE and CRE. In both cases, the mechanism would involve the interplay of common trans-acting factor(s), some of which are liver-enriched [HNF3, DBP or C/EBP related bZIP proteins] with their cognate target sequence.
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