Abstract
Insulin-like growth factor-I receptor (IGF-IR) gene expression is regulated by various stimuli, including hormones, growth factors, and nutritional status. We have investigated the molecular mechanism by which two growth factors, insulin-like growth factor-I (IGF-I) and basic fibroblast growth factor (bFGF) regulate IGF-IR gene expression. bFGF increases the endogenous IGF-IR mRNA levels and IGF-IR promoter activity. This effect is mediated by a region of the IGF-IR promoter located between nucleotides -476 and -188 in the 5'-flanking region. In contrast, IGF-I decreases the IGF-IR mRNA levels. IGF-I down-regulates IGF-IR transcriptional activity as deduced from experiments in which the levels of pre-mRNA and mRNA were measured. IGF-I reduced pre-mRNA and mRNA levels in parallel, while the mRNA stability was found to be unchanged by IGF-I treatment. While these results strongly suggest an effect of IGF-I on IGF-IR transcriptional activity, no specific IGF-I response element was demonstrated in the 5'-untranslated region or 5'-flanking region studied. Thus, bFGF and IGF-I have differential effects on IGF-IR gene transcription, with the IGF-I response region as yet unidentified.
Highlights
The insulin-like growth factors (IGFs)1 and the IGF-I receptor (IGF-IR) are important modulators of cell growth and differentiation in many tissues [1]
Total RNA was isolated, and the levels of IGF-IR mRNA were measured by solution hybridization-RNase protection assays as described under “Experimental Procedures.” bFGF increased endogenous IGF-IR mRNA levels by about 40 –50% at 4 h of incubation, with the maximum effect (ϳ90%) at 16 h (Fig. 1A)
Effect of bFGF on IGF-I Receptor Levels—To assess the relevance of the increase in IGF-IR mRNA levels by bFGF we studied the bFGF effect on IGF-IR protein
Summary
Vol 272, No 8, Issue of February 21, pp. 4663–4670, 1997 Printed in U.S.A. Differential Regulation of Insulin-like Growth Factor-I (IGF-I) Receptor Gene Expression by IGF-I and Basic Fibroblastic Growth Factor*. In cultured IM-9 lymphoid, FRTL-5 thyroid, and endothelial cells, IGF-IR expression is regulated by the concentration of IGF-I in the culture medium [7, 8], with increased IGF-I levels causing a decrease in receptor number. Under certain circumstances this down-regulation involves a translocation of cell-surface receptors to an intracellular pool [9], whereas in other cell types the effect is due to decreased IGF-IR gene expression [10]. PDGF increases IGF-IR gene expression and ligand binding in cells in culture [14], and this effect is due, at least in part, to PDGF stimulation of IGF-IR gene transcriptional activity. The region responsible for the response to bFGF is located in the proximal 476 bp of the 5Ј-flanking region, whereas the region responsible for the response to IGF-I is apparently located outside of the Ϫ2350-bp to ϩ640-bp region of the IGF-IR gene promoter
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