In vivo regulation of growth hormone-stimulated gene transcription by STAT5b

Abstract

The long-term effects of growth hormone (GH) are mediated through coordinated changes in gene expression that are the outcome of interactions between hormone-activated signal transduction pathways and specific feedback loops. Recent studies in mice have implicated the transcription factor STAT5b as part of the GH-regulated somatic growth pathway, because mice lacking this protein showed diminished growth rates. To assess the role of Stat5b in GH-stimulated gene expression, we have delivered modified versions of the protein to the liver of pituitary-deficient male rats by quantitative adenovirus-mediated gene transfer. In pilot studies in cell culture, both constitutive-active and dominant-negative STAT5b showed appropriate binding properties toward a specific DNA response element. After in vivo expression, neither protein prevented nuclear accumulation of STATs 1 and 3 in the liver. Dominant-negative STAT5b completely inhibited GH-stimulated transcription of genes encoding the growth-promoting proteins IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS), which comprise the major circulating IGF-I complex, and blocked expression of the GH inhibitors SOCS-1, SOCS-2, and CIS, but had little effect on induction of SOCS-3. Constitutive-active STAT5b stimulated robust transcription of IGF-I, ALS, and IGFBP-3 in the absence of hormone but did little to modify GH-mediated activation of SOCS family genes. An adenovirus encoding EGFP was without effect. These results, in addition to establishing STAT5b as one of the key agents of GH-stimulated gene transcription, demonstrate the feasibility of using in vivo gene transfer to target and dissect the functions of distinct components of complex hormone-activated signal transduction pathways.

Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration

“…In Stat5 fl/fl; Alb-Cre mice the mRNA levels of SOCS2 and Cish were reduced by approximately 80% and 70%, respectively. The IGF-1 gene is a direct target of Stat5 9 and, as expected, its expression was reduced in mutant liver tissue (Table 1B). We used real-time quantitative polymerase chain reaction to verify and quantitate the expression of SOCS2, Stat1, and peroxisome proliferator-activated receptor ␥ (PPAR␥).…”

“…8 We determined liver regeneration by bromodeoxyuridine incorporation assay as described. 9 We counted cells from 20 fields at a magnification of ϫ200 for each sample and scored them for the percentage of bromodeoxyuridine-positive cells. We determined statistical significance by 2-tailed Student t tests.…”

Human Sarcopenia Reveals an Increase in SOCS-3 and Myostatin and a Reduced Efficiency of Akt Phosphorylation

“…IGF-1 gene transcription is controlled by GH 9 via a Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5b (STAT5b) signaling pathway. 10,11 In aging human skeletal muscle, a reduction in IGF mRNA has been observed 12 and suggested to result from a reduced GH secretion or a reduced GH sensitivity. 13 The mechanisms regulating GH and IGF levels in aged skeletal muscle are unknown.…”

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

“…SOCS impede activation of the JAK/ STAT pathway and stimulate GH-receptor internalization (Bartke et al, 2013). STAT-5b regulates the transcription of the insulin-like growth factor 1 (IGF-1) gene (Zhu et al, 2001;Woelfle and Rotwein, 2004).…”

“…Via JAK-2, GH activates mainly STAT-5a and -5b, the PI3K/AKT and the ERK1/2-pathways (Zhu et al, 2001). Via GH/GHR, STAT5b regulates the transcription of the IGF-1 gene, a main way through which GH stimulates growth (Zhu et al, 2001;Woelfle and Rotwein, 2004). The dysregulation of the ERK1/2-pathway plays an important role in tumorogenicity (Santen et al, 2002;Dhillon et al, 2007).…”