Direct glucocorticoid receptor–Stat5 interaction in hepatocytes controls body size and maturation-related gene expression

Abstract

The glucocorticoid receptor regulates transcription through DNA binding as well as through cross-talk with other transcription factors. In hepatocytes, the glucocorticoid receptor is critical for normal postnatal growth. Using hepatocyte-specific and domain-selective mutations in the mouse we show that Stat5 in hepatocytes is essential for normal postnatal growth and that it mediates the growth-promoting effect of the glucocorticoid receptor through a direct interaction involving the Nterminal tetramerization domain of Stat5b. This interaction mediates a selective and unexpectedly extensive part of the transcriptional actions of these molecules since it controls the expression of gene sets involved in growth and sexual maturation.Supplemental material is available at http://www.genesdev.org.Received January 24, 2007; revised version accepted March 16, 2007. Glucocorticoids are secreted by the adrenal cortex and constitute the final effector of the hypothalamus-pituitary-adrenal (HPA) gland axis. They are essential for the maintenance of homeostasis during environmental challenges and are also required for normal development and survival. The effects of glucocorticoids are mediated by the ubiquitously expressed glucocorticoid receptor (GR) and the mineralocorticoid receptor that has a restricted expression. Upon ligand binding, the GR can act in a multitude of ways to induce or repress the transcription of target genes. These ways include binding to glucocorticoid response elements (GREs) in regulatory gene regions and protein-protein interactions with other transcription factors. DNA binding of the GR is believed to mediate most of the activating actions while cross-talk with transcription factors is believed to mediate the repressing actions (Reichardt et al. 1998(Reichardt et al. , 2001. One exception, in which GR activates transcription without classic DNA binding, is its functional interaction with Stat5 (Stocklin et al. 1996). It was originally described for activation of the ␤-casein promoter, where the activation was shown to depend on physical GR-Stat5 interaction and DNA binding of Stat5, whereas GR binding to a classic GRE was dispensable (Stoecklin et al. 1997). In addition, it has been reported that Stat5 can inhibit glucocorticoid-mediated activation of GREs (Stocklin et al. 1996;Biola et al. 2001). However, these studies (Stocklin et al. 1996;Stoecklin et al. 1997;Biola et al. 2001) were carried out in vitro and only investigated the behavior of a few Stat5 target genes.We recently showed that deletion of Nr3c1, the gene encoding GR in hepatocytes leads to a defect in postnatal growth (Tronche et al. 2004). Since Stat5 is a critical link in growth hormone (GH) signaling, it was suggested that this growth deficiency may depend on abrogated Stat5 signaling. Hepatocyte-specific deletion of the genes encoding GR resulted in reduced expression levels of some Stat5 targets regulated by GH, such as insulin-like growth factor-1 (IGF-1) and the acid-labile subunit (ALS) (Tronche et al. 2004). Further...

STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

“…The STAT5-RE's discussed above are also termed gamma interferon activation site elements, particularly in reference to prolactin control of genes uniquely expressed in the mammary gland (35). Furthermore, STAT5-GR interactions have been documented to regulate transcription of glucocorticoid responsive genes in hepatocytes that are responsible for growth (36). To our knowledge, ZnT2 is the only gene expressed in pancreatic acinar cells that has been shown to be regulated by DEX via the STAT5-GR interaction.…”

The AlfpCre mouse revisited: Evidence for liver steatosis related to growth hormone deficiency

“…1). In contrast, Stat5 loxP/loxP ;GR loxP/loxP ;Tg:AlfpCre/0 animals show a severely reduced body weight 4 ( Fig. 1).…”

“…1D), a finding that was also observed in AlfpCre 1/2 c-Jun F/F mice. 4 Downstream of the impaired GH signaling, AlfpCre 1 livers showed increased levels of triglycerides (TGs), free fatty acids (FFAs), and cholesterol, indicating liver steatosis (Fig. 1E).…”

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…In addition, GR-mediated transcriptional activation is modulated both positively and negatively by phosphorylation (Ismaili & Garabedian 2004) of kinases and phosphatases. Although the activity of the GR is often thought in terms of direct gene transactivation, considerable crosstalk also occurs between the GR and a cohort of molecules to mediate their function as transcriptional factors, including octamer transcription factors, OCT1 and OCT2, cyclic adenosine monophosphate response element-binding protein and signal transducers and activators of transcription 5 (Engblom et al 2007, Chen et al 2012, Ratman et al 2013. Competition for limiting transcription co-activators is an important determinant of the fate of the crosstalk between the GR and other transcription factors.…”