Premium
The cAMP‐Responsive Unit of the Human Insulin‐Like Growth Factor–Binding Protein‐1 Coinstitutes a Functional Insulin‐Response Element
Author(s) -
SCHWEIZERGROYER GHISLAINE,
FALLOT GUILLAUME,
CADEPOND FRANÇOISE,
GIRARD CHRISTELLE,
GROYER ANDRÉ
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1378.075
Subject(s) - insulin , transcription factor , endocrinology , medicine , response element , biology , promoter , insulin receptor , microbiology and biotechnology , chemistry , gene , insulin resistance , gene expression , biochemistry
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.