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: 4.6). 08/2008; 283(32):22089-96. DOI: 10.1074/jbc.M801041200
Source: PubMed

ABSTRACT 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 IFNgamma and enhanced in SOCS1-deficient murine embryonic fibroblasts as compared with IFNgamma treated wild-type cells. Our results suggest a prominent role of SOCS1 in the early phase of cross-talk between GR and cytokine signaling.

Download full-text


Available from: Wolfgang Doppler, Jan 05, 2015
1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: A hybrid fault current limiter and active noise cancellation system is being developed at the Colorado School of Mines for use in high voltage DC power systems with very high SNR requirements. This system uses a resistive superconducting fault current limiter (FCL) and electrically isolated solenoid to produce a variable resistance across a length of bulk high T<sub>c</sub> superconducting YBCO filament. This paper describes the process of material testing of the YBCO filaments, modeling and modulator prototype development. Results from the material testing and modeling are also presented
    Power Modulator Symposium, 1996., Twenty-Second International; 07/1996
  • Source
    [Show abstract] [Hide abstract]
    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.
    Molecular Endocrinology 03/2009; 23(3):281-91. DOI:10.1210/me.2008-0283 · 4.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Suppressor of cytokine signaling 1 (SOCS1) belongs to a family of genes involved in inducible feedback inhibition of janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway. Recently, we were able to show that SOCS1 surprisingly translocates to the nucleus due to the presence of a functional nuclear localization signal (NLS). However, the precise nature of the NLS remained ill-defined. Here we investigated further details of the SOCS1 NLS and analyzed its functional importance. We show that nuclear transport of SOCS1 particularly depends on the second cluster of basic amino acid residues within the NLS. Neither the first nor a nearby identified third cluster of basic amino acids were sufficient for mediating nuclear localization of SOCS1. Altering the subcellular localization of SOCS1 by mutating clusters of arginine residues within the NLS did not affect the inhibition of interferon mediated STAT1 tyrosine-phosphorylation, but surprisingly led to impaired inhibitory activity of STAT mediated reporter gene induction and IFN-gamma induced CD54 regulation. A SOCS-box deletion mutant (E176X) also had reduced inhibitory activity. In contrast, nuclear factor kappaB (NFkappaB) signaling was not affected by SOCS1 wt or mutants. Thus, SOCS1 may accomplish its inhibitory function in the IFN-pathway in part through nuclear localization.
    Molecular Immunology 07/2009; 46(13):2474-80. DOI:10.1016/j.molimm.2009.05.020 · 3.00 Impact Factor