Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complex.

Abstract

Insulin-like growth factors (IGFs) are present in the circulation, largely as part of a high mol wt complex including IGF-binding protein-3 (IGFBP-3) and an acid-labile subunit (ALS). This study used in situ hybridization to investigate the cellular sites of synthesis of these factors in the rat and to evaluate changes in transcript levels during development and after hypophysectomy and GH treatment. IGFBP-3 transcripts are considerably more abundant and widely expressed than ALS at birth, but both are present in liver and kidney. Hepatic IGFBP-3 gene expression increases slightly, whereas ALS increases dramatically in the first few weeks after birth. IGFBP-3 mRNA is concentrated in portal venous and sinusoidal endothelium, but is not detected in hepatocytes, whereas ALS mRNA is diffusely expressed by hepatocytes, but is not detected in nonparenchymal cells. Both transcripts are localized in the renal cortex; however, IGFBP-3 mRNA is concentrated in interstitial cells, whereas ALS is expressed in proximal tubule epithelium. Hypophysectomy results in a 90% reduction in hepatic ALS and an approximately 50% decrease in IGFBP-3 mRNA level. ALS, but not IGFBP-3, transcripts were also reduced in the kidney. GH receptor mRNA is coexpressed with ALS in liver and kidney, suggesting that the effects of GH on ALS gene expression may be direct. In summary, the fact that IGFBP-3 gene expression is far more widespread than that of ALS in both spatial and temporal parameters suggests that IGFBP-3 has a role apart from contribution to the ternary complex. We have also shown that IGFBP-3 and ALS are synthesized by distinct hepatic cell types in an anatomical organization that may serve to ensure efficient formation of the ternary complex in the blood passing through the sinusoids. Finally, the present data suggest that regulation of ALS synthesis may be the primary site of GH regulation of ternary complex formation.

Insulin‐like growth factor (IGF)‐I and IGF‐binding protein 3 and the risk of premenopausal breast cancer: A meta‐analysis of literature

“…22 Most circulating IGFs are produced by hepatocytes in response to growth hormone stimulation. [23][24][25] Circulating IGFBP-3 is produced by hepatic endothelium and Kupffer cells. 24,25 A number of in vitro and in vivo studies have demonstrated that IGF-I is an effective mitogen in normal epithelial cells and has strong antiapoptotic effects on breast cancer cells.…”

“…[23][24][25] Circulating IGFBP-3 is produced by hepatic endothelium and Kupffer cells. 24,25 A number of in vitro and in vivo studies have demonstrated that IGF-I is an effective mitogen in normal epithelial cells and has strong antiapoptotic effects on breast cancer cells. 22,26 -28 However, the effect of IGF-I may be modulated by IGFBP-3 in circulation because most of the IGF-I is bound to IGFBP-3 and once bound it is not in its active form.…”

Mechanism of radiation-induced bystander effect: Role of the cyclooxygenase-2 signaling pathway

“…In humans, the majority of the circulating IGFs are bound to IGFBP-3, which is produced mainly in the liver (32). IGFBP-3 inhibits IGF activity at the cellular level by binding competitively to IGFs and, thereby, preventing their binding to the IGF receptors in the cell surface.…”

Changes of serum growth factors (IGF-I,-II and IGFBP-2,-3) prior to and after stem cell transplantation in children with acute leukemia

“…It is highly expressed by the liver and other extrahepatic tissues. 5 IGF-II has a lower growth hormone dependency compared to IGF-I. The highest concentrations could be found during the fetal development.…”