GH is a regulator of IGF2 promoter-specific transcription in human liver

Abstract

The regulation of the insulin-like growth factor-II gene (IGF2) is complex and involves the usage of four promoters resulting in different 5 untranslated regions, but with a common translated product. The IGF2 gene product is a mitogenic and survival factor that has been suggested to be important for a normal fetal development and cancer. In this paper we present evidence suggesting that the human IGF2 gene is regulated by GH, and that this regulation occurs in a promoter-specific way. Three lines of evidence support this finding. First, in vivo data from patients treated with GH (one injection or daily injections for 5 consecutive days) showed an increase in the IGF2 P2 promoter derived transcript after acute treatment, and of the P4 promoter transcript after shortterm treatment while the P1 promoter derived transcript did not show any significant change. Secondly, isolated human liver cells treated with GH for 2 h displayed an upregulation of the P2 promoter derived transcript. Thirdly, employing transfection experiments in GHreceptor positive CHO cells with P2 and P4 promoterluciferase constructs, an upregulation by GH was evident, while a P1 promoter construct was unresponsive. We suggest that GH may be a physiological regulator of IGF2 in humans.

FSH Regulates IGF-2 Expression in Human Granulosa Cells in an AKT-Dependent Manner

“…The results demonstrated that P1-driven IGF-2 transcripts were absent in human cumulus cells, and P2-driven transcripts were barely detectable after 40 cycles, even in human liver cDNA. This is consistent with previous reports of low P2-driven IGF-2 expression in liver (26,27). In contrast, P3-and P4-driven IGF-2 transcripts were abundant (Figure 4B).…”

“…In the liver, GH regulates IGF-2 expression, but this is not the case in granulosa cells (26,39,40). This suggests that mechanisms of IGF-2 expression are cell type-specific, and a closer inspection of these mechanisms specifically in human granulosa cells is necessary to understand IGF-2 regulation during follicle development.…”

Differential regulation of Igf1 and Igf2 mRNA levels in tilapia hepatocytes: effects of insulin and cortisol on GH sensitivity

“…05 to 1!10 K9 M (Weber & Grau 1999, Uchida et al 2003, Fox et al 2009), suggesting that physiological regulation of liver igf1 and igf2 by GH occurs on the left side of the concentration-response curve. In humans, GH injection increased liver Igf2 transcripts from promoters P2 and P4, but did not change overall Igf2 transcript levels, and GH treatment increased P2 transcripts in primary human hepatocytes (Olivecrona et al 1999, von Horn et al 2002. As far as we are aware, this is the only recent report of GH-dependent liver Igf2 gene expression in mammals.…”

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

“…On the other side, serum IGF1 exerts a negative feedback on GH production, by directly inhibiting the pituitary gland secretion and indirectly stimulating SST and inhibiting GHRH secretion [33]. IGF2 is a circulating peptide hormone whose regulation can be under the control of GH [38]. IGF2 plays an important role in the body growth and metabolism, especially during the prenatal life.…”