Tri-iodothyronine and cycloheximide enhance insulin-like growth factor-binding protein-1 gene expression in human hepatoma cells

Abstract

The growth-regulating actions of IGFs are modulated by their binding proteins (IGFBPs). The serum concentration of IGFBP-1 is down-regulated by insulin, and in-vitro studies have demonstrated that IGFBP-1 secretion from various tissues and cells can be stimulated by theophylline, forskolin, oestrogen and progesterone. We have studied the effects and mechanisms of thyroid hormone action on IGFBP-1 gene expression and secretion by human hepatoma cells in vitro. Tri-iodothyronine dose-dependently enhanced IGFBP-1 secretion in serum-free HepG2 cell cultures after 24-48 h of exposure, as measured by a specific immunofluorometric assay. This was accompanied by an increase (+ 50%) in the amount of IGFBP-1 mRNA, which could be prevented by cycloheximide, a protein synthesis inhibitor. Cycloheximide transiently enhanced (+ 200%) the accumulation of IGFBP-1 mRNA at 3-12 h of incubation, when no effect of tri-iodothyronine was observed. It is concluded that thyroid hormone stimulates IGFBP-1 secretion slowly by enhancing IGFBP-1 gene expression by a protein mediator. The acute stimulation of IGFBP-1 gene transcription by cycloheximide associates this gene with a number of growth-related genes encoding growth- and tumour-associated peptides.

Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

“…As IGF-I has a stimulatory effect on D1 expression (55), these higher levels of free IGF-I might be seen as an adaptation to normalize D1 activity in carriers of the D1a-T haplotype allele. Conversely, thyroid hormone stimulates the expression of IGFbinding protein-I (IGFBP-I) in human hepatoma cells (56). A lower activation of thyroid hormone by liver D1 could result in lower levels of IGFBP-1, and thus a higher level of free IGF-I (51), as the majority of IGFBP-1 is produced in the liver.…”

Tri-iodothyronine and a deleted form of hepatocyte growth factor act synergistically to enhance liver proliferation and enable in vivo retroviral gene transfer via the peripheral venous system

“…24 T3 acts via hormone responsive nuclear transcription factors present in most tissues and regulates the expression of numerous genes. [25][26][27][28][29] HGF is an important mitogen, motogen and morphogen for hepatocytes. [30][31][32][33][34] Serum levels of HGF rise rapidly after partial hepatectomy and precede the surge in hepatic DNA synthesis.…”

Growth hormone/insulin-like growth factor axis in patients with subclinical thyroid dysfunction

“…Main results of these in vivo investigations suggest that there is an increase in serum levels of IGF-I in patients with hyperthyroidism [8,13,15,17,18], and a decrease of these values in patients with hypothyroidism [8][9][10]12]. IGFBP-3 concentrations have been found to be increased in hyperthyroidism [8,12,13,15], and decreased [12] or unmodified [8] in hypothyroidism.…”