Interaction and Functional Interference of Glucocorticoid Receptor and SOCS1

Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2008; 283(32):22089-96. DOI: 10.1074/jbc.M801041200
Source: PubMed


Cytokine and glucocorticoid (GC) hormone signaling act in an integrated fashion to control inflammation and immune response.
Here we establish a new mode of interaction of these two pathways and propose Suppressor of Cytokine Signaling (SOCS)-1 as
an essential player in mediating cross-talk. We observed that glucocorticoid receptor (GR) and SOCS1 form an intracellular
complex through an interaction, which required the SH2 domain of SOCS1 and the ligand binding domain of GR. Furthermore, GC
stimulation was found to increase the nuclear level of SOCS1. SOCS1 binding to the GR did not require ligand binding of the
receptor; however, it was abolished after long term GC stimulation, suggesting a functional role of the interaction for the
early phase of GC action. The interaction between GR and SOCS1 appeared to negatively influence the transcription of the two
GR-regulated genes, FKBP5 and MKP1, because the GC-dependent expression of these genes was inhibited by the SOCS1 inducer
IFNγ and enhanced in SOCS1-deficient murine embryonic fibroblasts as compared with IFNγ treated wild-type cells. Our results
suggest a prominent role of SOCS1 in the early phase of cross-talk between GR and cytokine signaling.

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    • "Furthermore, other reports showed a role for the SOCS proteins in regulating other signal transduction molecules (e.g. FAK, IRS, p65, GR) that are highly relevant to carcinogenesis [24-28] "
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    ABSTRACT: Background Suppressors of cytokine signaling (SOCS) are important negative feedback regulators of the JAK/STAT signaling pathway, and have been recently investigated for their role in the development of different cancers. In this study, we examined the expression of SOCS1-7 genes in normal and breast cancer tissue and correlated this with several clinico-pathological and prognostic factors. Methods SOCS1-7 mRNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples (n = 127) and normal background breast tissue (n = 31). Transcript levels of expression were determined using real-time PCR and analyzed against TNM stage, tumour grade and clinical outcome over a 10 year follow-up period. Results SOCS1,4,5,6 and 7 expression decreased with increased TNM stage (TNM1 vs. TNM3 p = 0.039, TNM1 vs. TNM4 p = 0.016, TNM2 vs. TNM4 p = 0.025, TNM1 vs. TNM3 p = 0.012, and TNM1 vs. TNM3 p = 0.044 respectively). SOCS2 and 3 expression decreased with increased Nottingham Prognostic Index (NPI) (NPI1 vs. NPI3 p = 0.033, and NPI2 vs. NPI3 p = 0.041 respectively). SOCS7 expression decreased with higher tumour grade (Grade 3 vs. Grade 2 p = 0.037). After a median follow up period of 10 years, we found higher levels of SOCS1,2 and 7 expression among those patients who remained disease-free compared to those who developed local recurrence (p = 0.0073, p = 0.021, and p = 0.039 respectively). Similarly, we found higher levels of SOCS 2,4, and 7 expression in those who remained disease-free compared to those who developed distant recurrence (p = 0.022, p = 0.024, and p = 0.033 respectively). Patients who remained disease-free had higher levels of SOCS1 and 2 expression compared to those who died from breast cancer (p = 0.02 and p = 0.033 respectively). The disease free survival (DFS) and overall survival (OS) curves showed that higher levels of SOCS1, 3 and 7 were significant predictors of higher DFS (p = 0.015, p = 0.024 and 0.03 respectively) and OS (p = 0.005, p = 0.013 and p = 0.035 respectively). Higher levels of SOCS 4 were significant in predicting better OS (p = 0.007) but not DFS. Immunohistochemical staining of representative samples showed a correlation between SOCS1, 3, 7 protein staining and the SOCS1, 3, 7 mRNA expression. Conclusion Higher mRNA expression levels of SOCS1, 3, 4 and 7 are significantly associated with earlier tumour stage and better clinical outcome in human breast cancer.
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    ABSTRACT: Taking into consideration that glucocorticoid (GC) hormones have been used clinically for over half a century and that more than 20 yr have passed since the cloning of the GC receptor (GR), it is hard to imagine that novel aspects in the molecular mechanism by which GCs mediate their antiinflammatory actions are still being unveiled today. Partly, this is because almost on a daily basis, novel insights arise from parallel fields, e.g. nuclear receptor cofactor and chromatin regulation and their concomitant impact on gene transcription events, eventually leading to a revisitation or refinement of old hypotheses. On the other hand, it does remain striking and puzzling why GCs use different mechanisms in so many different cell types and on many different target genes to elicit an antiinflammatory effect. Meanwhile, the obvious question for the clinic remains: is the separation of GR functionalities through differential ligand design the strategy of choice to avoid most GC-mediated side effects? This minireview aims to highlight some of the latest findings on aspects of the antiinflammatory working mechanisms of GCs.
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