title: The cAMP-responsive unit of the human insulin-like growth factor-binding protein-1 coinstitutes a functional insulin-response element.
abstract: Insulin-like growth factor-binding protein-1 (IGFBP-1) is one of the genes involved in glucose homeostasis. In vivo, its level is increased by counter-regulatory hormones (glucocorticoids and glucagon via its second messenger cAMP) and decreased by insulin, these variations being primarily correlated with IGFBP-1 gene transcription. Previous reports described a functional insulin response element (IRE), immediately 5'- to the glucocorticoid response element (GRE). This IRE has been shown to mediate partial inhibition (1) of basal IGFBP-1 promoter activity and (2) of glucocorticoid-induced stimulation of gene transcription by insulin. In this work, using human HepG2 hepatoma cells as a model system, we showed: (1) that insulin inhibited both basal and cAMP-induced hIGFBP-1 promoter (nt-1 to -341) activity; (2) that in the absence of insulin, forkhead box class O (FOXO) transcription factors enhance constitutive hIGFBP-1 promoter activity without interfering with the stimulatory effect of cAMP; (3) that PI-3' kinase signaling is involved in the inhibition of constitutive and cAMP-induced promoter activities by insulin; (4) that wild-type FOXO-1 mediates the inhibitory effect of insulin on the promoter, although FOXO-1(Ala3), a nonphosphorylatable mutant of FOXO-1, does not; (5) that the cAMP-responsive unit (CRU), that includes a putative IRE (nt-265 to -282) and a cAMP responsive element (CRE; nt-258 to -263), is sufficient per se to mediate both cAMP stimulation of a heterologous promoter, and inhibition of both basal and cAMP-induced promoter activities by insulin; and (6) that the inhibitory effects of insulin on the isolated CRU are mediated by the FOXOs. This study is the first evidence for the occurrence of a second IRE within hIGFBP-1 promoter sequences, IRE(CRU), located 5'- to the CRE.
authors.affiliation: INSERM U.788, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cédex, France. groyer@kb.inserm.fr
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Schweizer-Groyer
authors.forename: Guillaume
authors.initials: G
authors.lastname: Fallot
authors.forename: Françoise
authors.initials: F
authors.lastname: Cadepond
authors.forename: Christelle
authors.initials: C
authors.lastname: Girard
authors.forename: André
authors.initials: A
authors.lastname: Groyer
mesh_terms: D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D020218:Response Elements / Q000502:physiology*
chemical_list: C032231:IGFBP1 protein, human; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D000242:Cyclic AMP