Endothelin-1 stimulates suppressor of cytokine signaling-3 gene expression in adipocytes

2012 ◽  
Vol 178 (3) ◽  
pp. 450-458 ◽  
Author(s):  
Hsin-Huei Chang ◽  
Yao-Ming Huang ◽  
Chi-Peng Wu ◽  
Ya-Chu Tang ◽  
Chi-Wei Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Endothelin 1

scholarly journals Regulation and role of suppressor of cytokine signaling-3 in hypothalamic 4B cells

2009 ◽  
Vol 201 (3) ◽  
pp. 369-376 ◽  
Author(s):  
Kazunori Kageyama ◽  
Komaki Hanada ◽  
Yasumasa Iwasaki ◽  
Toshihiro Suda
Keyword(s):  
Gene Expression ◽  
Stress Responses ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Suppressor Of Cytokine Signaling ◽  
Hypothalamic Cells ◽  
Parvocellular Neurons ◽  
Response To Stress ◽  
Inhibitory Signaling

Corticotropin-releasing factor (CRF) plays a central role in regulating stress responses. In the hypothalamic paraventricular nucleus (PVN), CRF, produced in response to stress, stimulates the release of ACTH from the anterior pituitary. ACTH then stimulates the release of glucocorticoids from the adrenal glands; circulating glucocorticoids are critical for recovery from stress conditions. Cytokines are also implicated in the regulation of CRF expression. Among them, interleukin (IL)-6 plays a role in the regulation of CRF. Factors other than glucocorticoids are likely to be involved in limiting the stimulation of CRF during stress. Suppressor of cytokine signaling (SOCS)-3 acts as a potent negative regulator of cytokine signaling. Little is known about the ability of the inhibitory signaling pathways to limit activation of the CRF gene in parvocellular PVN neurons. Hypothalamic 4B cells are useful for exploring the mechanisms, because these cells show characteristics of the parvocellular neurons of the PVN. In the present study, we examined whether SOCS-3 is regulated by IL-6 and cAMP in hypothalamic 4B cells. We also explored the involvement of SOCS-3 in the regulation of CRF gene expression. SOCS-3 was found to be regulated by IL-6 and via the cAMP/protein kinase A pathway in the hypothalamic cells. SOCS-3 knockdown increased IL-6- or forskolin-induced CRF gene transcription and mRNA levels. Therefore, SOCS-3, induced by a cAMP stimulant and IL-6, would be involved in the negative regulation of CRF gene expression in hypothalamic cells.

Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling

2005 ◽  
Vol 289 (6) ◽  
pp. E1051-E1057 ◽  
Author(s):  
Christopher D. Morrison ◽  
Gregory J. Morton ◽  
Kevin D. Niswender ◽  
Richard W. Gelling ◽  
Michael W. Schwartz
Keyword(s):  
Gene Expression ◽  
Inhibitory Effect ◽  
Cytokine Signaling ◽  
Pi3k Signaling ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Suppressor Of Cytokine Signaling ◽  
Stat3 Signaling ◽  
Sprague Dawley Rats ◽  
Phosphatidylinositol 3

Phosphatidylinositol 3-OH-kinase (PI3K) and STAT3 are signal transduction molecules activated by leptin in brain areas controlling food intake. To investigate their role in leptin-mediated inhibition of hypothalamic neuropeptide Y ( Npy) and agouti-related peptide ( Agrp) gene expression, male Sprague-Dawley rats ( n = 5/group) were either fed ad libitum or subjected to a 52-h fast. At 12-h intervals, the PI3K inhibitor LY-294002 (LY, 1 nmol) or vehicle was injected intracerebroventricularly (ICV) as a pretreatment, followed 1 h later by leptin (3 μg icv) or vehicle. Fasting increased hypothalamic Npy and Agrp mRNA levels ( P < 0.05), and ICV leptin administration prevented this increase. As predicted, LY pretreatment blocked this inhibitory effect of leptin, such that Npy and Agrp levels in LY-leptin-treated animals were similar to fasted controls. By comparison, leptin-mediated activation of hypothalamic STAT3 signaling, as measured by induction of both phospho-STAT3 immunohistochemistry and suppressor of cytokine signaling-3 ( Socs3) mRNA, was not significantly attenuated by ICV LY pretreatment. Because NPY/AgRP neurons project to the hypothalamic paraventricular nucleus (PVN), we next investigated whether leptin activation of PVN neurons is similarly PI3K dependent. Compared with vehicle, leptin increased the number of c-Fos positive cells within the parvocellular PVN ( P = 0.001), and LY pretreatment attenuated this effect by 35% ( P = 0.043). We conclude that leptin requires intact PI3K signaling both to inhibit hypothalamic Npy and Agrp gene expression and activate neurons within the PVN. In addition, these data suggest that leptin activation of STAT3 is insufficient to inhibit expression of Npy or Agrp in the absence of PI3K signaling.

scholarly journals Activation of SOCS-3 by Resistin

2005 ◽  
Vol 25 (4) ◽  
pp. 1569-1575 ◽  
Author(s):  
Claire M. Steppan ◽  
Juan Wang ◽  
Eileen L. Whiteman ◽  
Morris J. Birnbaum ◽  
Mitchell A. Lazar
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Protein Kinase B ◽  
Inhibitory Effect ◽  
Cytokine Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Suppressor Of Cytokine Signaling ◽  
Pi3k Activation

ABSTRACT Resistin is an adipocyte hormone that modulates glucose homeostasis. Here we show that in 3T3-L1 adipocytes, resistin attenuates multiple effects of insulin, including insulin receptor (IR) phosphorylation, IR substrate 1 (IRS-1) phosphorylation, phosphatidylinositol-3-kinase (PI3K) activation, phosphatidylinositol triphosphate production, and activation of protein kinase B/Akt. Remarkably, resistin treatment markedly induces the gene expression of suppressor of cytokine signaling 3 (SOCS-3), a known inhibitor of insulin signaling. The 50% effective dose for resistin induction of SOCS-3 is ∼20 ng/ml, close to levels of resistin in serum. Association of SOCS-3 protein with the IR is also increased by resistin. Inhibition of SOCS function prevented resistin from antagonizing insulin action in adipocytes. SOCS-3 induction is the first cellular effect of resistin that is independent of insulin and is a likely mediator of resistin's inhibitory effect on insulin signaling in adipocytes.

scholarly journals Comprehensive analysis of suppressor of cytokine signaling proteins in human breast Cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mingyu Sun ◽  
Chuangang Tang ◽  
Jun Liu ◽  
Wenli Jiang ◽  
Haifeng Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Prognostic Factor ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Expression Levels ◽  
Pathway Enrichment ◽  
Stat Signaling ◽  
Socs Proteins ◽  
Mrna Expression Levels

Abstract Background Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA). Methods The gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA). Results Data related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro. Conclusions SOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer.

scholarly journals Isoproterenol is a positive regulator of the suppressor of cytokine signaling-3 gene expression in 3T3-L1 adipocytes

2002 ◽  
Vol 175 (3) ◽  
pp. 727-733 ◽  
Author(s):  
M Fasshauer ◽  
J Klein ◽  
U Lossner ◽  
R Paschke
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Mrna Expression ◽  
Adenylyl Cyclase ◽  
Insulin Signaling ◽  
Tnf Alpha ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Suppressor Of Cytokine Signaling ◽  
Beta Adrenergic

SOCS (suppressor of cytokine signaling)-3 has recently been shown to be an insulin- and tumor necrosis factor (TNF)-alpha-induced negative regulator of insulin signaling. To further clarify a potential involvement of SOCS-3 in the development of insulin resistance, we measured differentiation-dependent SOCS-3 mRNA expression in 3T3-L1 adipocytes and studied its regulation by various hormones known to impair insulin signaling using quantitative real-time RT-PCR. There was a differentiation-dependent downregulation of SOCS-3 mRNA by 50% over the 9 day adipocyte differentiation course. Interestingly, besides insulin and TNF-alpha, chronic treatment of differentiated 3T3-L1 cells with 10 microM isoproterenol for 16 h stimulated SOCS-3 gene expression by about 3.5-fold. Furthermore, isoproterenol stimulated SOCS-3 mRNA expression in a dose-dependent manner with significant activation detectable at concentrations as low as 10 nM isoproterenol. Moreover, a strong 27- and 47-fold activation of SOCS-3 mRNA expression could be seen after 1 h of isoproterenol and GH treatment respectively. The stimulatory effect of isoproterenol could be almost completely reversed by pretreatment of 3T3-L1 cells with the beta-adrenergic antagonist propranolol. Finally, isoproterenol's action could be mimicked by stimulation of G(S)-proteins with cholera toxin and of adenylyl cyclase with forskolin and dibutyryl cAMP. Taken together, our results demonstrate a differentiation-dependent downregulation of SOCS-3 in adipocytes and suggest that SOCS-3 gene expression is stimulated by beta-adrenergic agents via activation of a G(S)-protein-adenylyl cyclase-dependent pathway. As SOCS-3 is a novel inhibitor of insulin signaling, the data support a possible role of this protein as a selectively regulated mediator of catecholamine-induced insulin resistance.

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