Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation

Abstract

Chronically elevated levels of GH in GH-transgenic mice result in accelerated growth and increased adult body weight. We have previously described that the GH-induced JAK2/STAT5-signaling pathway is desensitized in the liver of transgenic mice overexpressing GH. However, these animals present increased circulating IGF-I levels, increased hepatic GHR expression, and liver organomegaly due to hypertrophy and hyperplasia, which frequently progress to hepatomas as the animals age, indicating that action of GH on the liver is not prevented. In the present study, we have evaluated other GH-signaling pathways that could be activated in the liver of GH-transgenic mice. Upon GH administration, normal mice showed an important increment in STAT3 phosphorylation level, but transgenic mice did not respond to acute GH stimulation. However, STAT3 was constitutively phosphorylated in transgenic mice, whereas its protein content was not increased. GH-transgenic mice showed overexpression of c-Src, accompanied by an elevation of its activity. Other signaling mediators including focal adhesion kinase, epidermal growth factor receptor, Erk, Akt, and mammalian target of rapamycin displayed elevated protein and basal phosphorylation levels in these animals. Thus, GH-overexpressing transgenic mice exhibit hepatic upregulation of signaling mediators related to cell proliferation, survival, and migration. The upregulation of these proteins may represent GH-signaling pathways that are constitutively activated in the presence of dramatically elevated GH levels throughout life. These molecular alterations could be implicated in the pathological alterations observed in the liver of GH-transgenic mice.

Growth hormone (GH) modulation of Epidermal growth factor (EGF) signalling in human mammary epithelial cells

“…Mice overexpressing GH have also shown an increased incidence of hepatocellular carcinomas at advanced ages (Snibson 2002, Bartke 2003. Up-regulation of proliferative and anti-apoptotic cascades were shown in mice-overexpressing GH (Miquet et al 2008). In this study the …”

“…Crosstalk between GH and EGF signalling pathways has been described; moreover, EGFR expression has been demonstrated to be regulated by GH (Jansson et al, 1988;Johansson et al, 1989;Miquet et al, 2008;González et al, 2010). GH caused tyrosine phosphorylation of the EGFR and subsequent MAPK signalling in mice livers and cell culture (Yamauchi et al, 1997).…”

“…GH was first described to induce Tyr1068 phosphorylation at EGFR in vitro and in vivo (Yamauchi et al, 1997, exogenous GH administration this expression deficit can be reversed (Jansson et al, 1988;Johansson et al, 1989). In transgenic mice overexpressing GH, EGFR levels are increased, whereas GH receptor-KO mice have diminished protein content (Miquet et al, 2008;González et al, 2010). In mice lacking the GH-receptor, consequently to less EGFR-expression, EGF-stimulated AKT, ERK1/2, STAT-3 and STAT-5 phosphorylation is diminished compared to normal mice (González et al, 2010).…”

“…In hypophysectomized or GH-deficient mutant mice, EGFR expression is diminished in liver tissue (Jannson et al, 1988;González et al, 2010) and GH-treatment reverses this downregulation of receptors (Jannson et al, 1988). Moreover, EGFR expression is increased in the liver of transgenic mice overexpresing GH (Miquet et al, 2008;González et al, 2010) EGF-induced phosphorylation of EGFR at its tyrosine residues results in downstream signalling cascades as the mitogen activated protein kinase Ras/Raf/MEK/ERK (p44/p42 MAPK), the PI3K/AKT and the STAT-pathways (Jorrisen et al, 2003;Schulze et al, 2005;Normanno et.al., 2006). These pathways are involved in cell survival and growth.…”

Effects of Growth Hormone (GH) Overexpression in Signaling Cascades Involved in Promotion of Cell Proliferation and Survival

“…Therefore, other signaling mediators induced by GH must be involved for the liver pathology observed in these animals. Studies performed in Mt-GHRH and PEPCK-bGH transgenic mice showed that these animals exhibit constitutive phosphorylation of STAT3 and upregulation of c-Src, FAK, EGFR, Akt, mTOR and Erk1/2 (Miquet et al, 2008). These molecules are all signaling mediators activated by GH that are involved in cell proliferation, differentiation, migration and survival, and their upregulation may represent alternative pathways to JAK2/STAT5 that are constitutively activated in the liver of transgenic mice overexpressing GH.…”