Abstract 2215: Glucocorticoid receptor function is essential for SOCS2-mediated negative regulation of hepatic GHR signaling

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 2215
• Main Authors: Mueller, Kristina M., Kornfeld, Jan-Wilhelm, Schuetz, Guenther, Moriggl, Richard
• Format: Journal Article
• Language: English
• Published: 15.04.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-2215

Abstract GHR signaling plays an essential role in somatic growth and development as well as in the maintenance of metabolic homeostasis. Target tissue responsiveness to GH is dependent on postreceptor mechanisms to circumvent unphysiological and off-target effects due to prolonged GHR activation. GHR signals amongst others through the JAK2/STAT5 pathway. SOCS2, a GH-STAT5-regulated gene, is a key negative regulator of GHR sensitivity. Transcription of distinct GH-STAT5-dependent gene subsets requires coactivator function of the glucocorticoid receptor (GR). This mechanism was shown to involve direct binding of GR to the STAT5 N-terminus. Earlier studies have implied that regulation of SOCS2 also requires synergistic action of STAT5 and GR. Therefore, our aim is to investigate the molecular interaction between STAT5 and GR to regulate SOCS2 expression. Hepatocyte-specific deletion of the GR causes reduced hepatic Socs2 mRNA expression approximately to the same extent as STAT5-deficient livers. Furthermore, STAT5 activity was increased and prolonged in GR-deficient livers upon exogenous GH administration. Genes which are dependent on functional STAT5-GR protein interaction often harbor potential STAT5 oligomer binding sites in their promoter regions. Using bioinformatic screening, we found three STAT5 oligomer binding sites in the murine distal Socs2 promoter region. First, binding of activated STAT5 to the putative binding sites was confirmed by DNA binding assays. Subsequently, we performed transactivation studies using a luciferase reporter construct containing the relevant region of the Socs2 promoter and an additional 3′ region to assess the requirement for putative enhancer sequences. Maximum luciferase activity was observed in the presence of activated STAT5b and GR only. However, this pronounced transactivation was severely impaired upon transfection of the aminoterminally truncated STAT5 isoform (STAT5ΔN). Additionally, direct physical interaction of activated STAT5 and GR on the Socs2 promoter was detected in GH/dexamethasone-treated control livers by re-ChIP assays. We demonstrate that full Socs2 transactivation requires STAT5-GR protein-protein interaction in hepatocytes. As the liver represents a primary site of GH-mediated STAT5 activation, deregulated GR signaling could lead to imbalanced liver GH sensitivity due to aberrant SOCS2-mediated feedback inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2215. doi:1538-7445.AM2012-2215