Insulin regulation of growth hormone receptor gene expression: involvement of both the PI-3 kinase and MEK/ERK signaling pathways

Abstract

The mechanism(s) of insulin's effects on growth hormone receptor (GHR) gene expression are poorly understood. Using rat hepatoma cells, we have previously shown that insulin treatment reduces GHR mRNA and protein in a time- and concentration-dependent manner, at least in part via down-regulation of GHR transcription. The present study determines whether the phosphatidylinositol-3 kinase (PI-3 kinase) and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways are involved in mediating these effects of insulin. Inhibition of the PI-3 kinase pathway partially blocked insulin's reduction of GHR mRNA, as did inhibition of the MEK/ERK pathway, resulting in higher GHR mRNA levels. Inhibition of both pathways was necessary to completely block insulin effects. Similar results were obtained for GHR protein. Collectively, these data suggest that insulin signaling via either the PI-3 kinase or MEK/ERK pathway may result in partial reduction of GHR gene expression, whereas signaling via both pathways may be required to achieve the full insulin effect.

Growth hormone receptor modulators

“…In rat hepatoma cells, low dose insulin administration results in GH-induced stimulation of JAK2 phosphorylation however high dose insulin treatment results in inhibitory effect [69,86]. The effect of insulin on GHR function appears to be mediated by the PI-3 kinase and MAPK/ERK pathways [69,87,88]. It has been shown that insulin increases GH signalling by enhancing GHinduced activation of MAPK/ERK pathway through post signalling cross-talk [88].…”

Prognostic role of metformin intake in diabetic patients with colorectal cancer: An updated qualitative evidence of cohort studies

“…Numerous epidemiologic studies have reported that metformin is associated with decreased risk of cancer incidence [2–7]. Metformin is supposed to inhibit cellular growth and proliferation by lowering insulin levels through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway pathways [8, 9]. Recent published study has also shown that metformin exhibits an anti-apoptotic effect on podocytes under high glucose conditions through activation of adenosine monophosphate-activated protein kinase (AMPK) and inhibition of mTOR signaling [10].…”

The Role of Ghrelin in Neuroprotection after Ischemic Brain Injury

“…The GHS-R1a is expressed throughout the brain including in feeding and metabolism-associated areas like the arcuate nucleus (ARC) [18,19,20], as well as regions important in memory (Cornu Ammonis (CA)2, CA3, dentate gyrus of the hippocampus) and reward (ventral tegmental area, substantia nigra pars compacta (SNpc), dorsal raphe) [19,21,22]. The GHS-R1a is a g-protein coupled seven transmembrane receptor.…”