Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo

GH may improve intestinal growth or function in patients with short bowel syndrome. Excessive trophic effects of GH or IGF-I may contribute to neoplastic growth or increased colorectal cancer risk in acromegaly. Identification of mechanisms that limit the tumorigenic potential of GH and IGF-I is desirable. Suppressor of cytokine signaling-2 (SOCS2) limits GH action on body and organ growth, but its role in GH action on intestine is unknown. We tested the hypothesis that SOCS2 limits GH-induced intestinal growth or neoplasia in vivo. GH-transgenic (GH-TG) mice were crossed with SOCS2 null mice to generate wild-type (WT) or transgenic (TG) mice with zero (HO-WT; HO-TG), one (HT-WT; HT-TG), or two (WT-WT; WT-TG) functional SOCS2 genes. No HO-TG mice were derived from crossbreeding. WT-WT, HT-WT, WT-TG, and HT-TG were compared. Body weight, small intestine and colon growth, and levels of jejunal IGF-I and sucrase-isomaltase mRNAs were assessed. Colon was analyzed for abnormal lesions. HT-WT did not differ from WT-WT. Compared with WT-TG, HT-TG had significantly increased body weight, small intestine growth, and local IGF-I expression and decreased sucrase-isomaltase expression. HT-TG colon spontaneously developed multiple hyperplastic and lymphoid polyps. GH-induced activation of STAT5 DNA binding activity was enhanced in intestine of SOCS2 null mice compared with WT control. Haplotype insufficiency for SOCS2 promotes trophic actions of GH in small intestine and promotes preneoplastic growth in colon during excess GH. Small variations in SOCS2 expression levels may significantly influence the outcome of therapeutic GH or acromegaly in intestine.

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Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00218.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. G472-G481 ◽

Cited By ~ 26

Author(s):

Carmen Z. Michaylira ◽

James G. Simmons ◽

Nicole M. Ramocki ◽

Brooks P. Scull ◽

Kirk K. McNaughton ◽

...

Keyword(s):

Small Intestine ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Ex Vivo ◽

Cytokine Signaling ◽

Intestinal Epithelial ◽

Growth Responses ◽

Intestinal Growth ◽

Igf I

Suppressors of cytokine signaling (SOCS) typically limit cytokine receptor signaling via the JAK-STAT pathway. Considerable evidence demonstrates that SOCS2 limits growth hormone (GH) action on body and organ growth. Biochemical evidence that SOCS2 binds to the IGF-I receptor (IGF-IR) supports the novel possibility that SOCS2 limits IGF-I action. The current study tested the hypothesis that SOCS2 normally limits basal or IGF-I-induced intestinal growth and limits IGF-IR signaling in intestinal epithelial cells. Intestinal growth was assessed in mice homozygous for SOCS2 gene deletion (SOCS2 null) and wild-type (WT) littermates at different ages and in response to infused IGF-I or vehicle or EGF and vehicle. The effects of SOCS2 on IGF-IR signaling were examined in ex vivo cultures of SOCS2 null and WT intestine and Caco-2 cells. Compared with WT, SOCS2 null mice showed significantly enhanced small intestine and colon growth, mucosal mass, and crypt cell proliferation and decreases in radiation-induced crypt apoptosis in jejunum. SOCS2 null mice showed significantly greater growth responses to IGF-I in small intestine and colon. IGF-I-stimulated activation of IGF-IR and downstream signaling intermediates were enhanced in the intestine of SOCS2 null mice and were decreased by SOCS2 overexpression in Caco-2 cells. SOCS2 bound directly to the endogenous IGF-IR in Caco-2 cells. The intestine of SOCS2 null mice also showed enhanced growth responses to infused EGF. We conclude that SOCS2 normally limits basal and IGF-I- and EGF-induced intestinal growth in vivo and has novel inhibitory effects on the IGF-IR tyrosine kinase pathway in intestinal epithelial cells.

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Faculty Opinions recommendation of Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1158396.618550 ◽

2009 ◽

Author(s):

Achsah Keegan ◽

Nicola Heller

Keyword(s):

Macrophage Activation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

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Suppressor of cytokine signaling 1 suppresses muscle differentiation through modulation of IGF-I receptor signal transduction

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2005.01.046 ◽

2005 ◽

Vol 328 (4) ◽

pp. 953-961 ◽

Cited By ~ 14

Author(s):

Makiko Inaba ◽

Hiroshi Saito ◽

Minoru Fujimoto ◽

Satoru Sumitani ◽

Tomoharu Ohkawara ◽

...

Keyword(s):

Signal Transduction ◽

Muscle Differentiation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Receptor Signal ◽

Igf I

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Interference with NTSR1 Expression Exerts an Anti-Invasion Effect via the Jun/miR-494/SOCS6 Axis of Glioblastoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000493838 ◽

2018 ◽

Vol 49 (6) ◽

pp. 2382-2395 ◽

Cited By ~ 4

Author(s):

Qing Ou-yang ◽

Xuzhi He ◽

Anqi Yang ◽

Bing Li ◽

Minhui Xu

Keyword(s):

Western Blotting ◽

Molecular Mechanisms ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Cytokine Signaling ◽

Glioblastoma Cells ◽

Suppressor Of Cytokine Signaling ◽

Underlying Mechanisms ◽

Neurotensin Receptor 1

Background/Aims: Glioblastoma is the most common and aggressive brain tumor and carries a poor prognosis. Previously, we found that neurotensin receptor 1 (NTSR1) contributes to glioma progression, but the underlying mechanisms of NTSR1 in glioblastoma invasion remain to be clarified. The aim of this study was to investigate the molecular mechanisms of NTSR1 in glioblastoma invasion. Methods: Cell migration and invasion were evaluated using wound-healing and transwell assays. Cell proliferation was detected using CCK-8. The expression of NTSR1, Jun, and suppressor of cytokine signaling 6 (SOCS6) was detected using western blotting. The expression of miR-494 was detected by Quantitative real-time PCR. Chromatin immunoprecipitation assay was performed to examine the interaction between Jun and miR-494 promoter. Dual-luciferase reporter assay and western blotting were performed to identify the direct regulation of SOCS6 by miR-494. An orthotopic xenograft mouse model was conducted to assess tumor growth and invasion. Results: NTSR1 knockdown attenuated the invasion of glioblastoma cells. Jun was positively regulated by NTSR1, which promoted miR-494 expression through binding to miR-494 promoter. SOCS6 was confirmed as a direct target of miR-494, thus, NTSR1-induced miR-494 upregulation resulted in SOCS6 downregulation. Both miR-494 and SOCS6 were involved in the NTSR1-induced invasion of glioblastoma cells. In vivo, tumor invasion and growth were inhibited by NTSR1 knockdown, but were restored with miR-494 overexpression. Conclusion: NTSR1 knockdown inhibited glioblastoma invasion via the Jun/miR-494/SOCS6 axis.

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Growth Enhancement in Suppressor of Cytokine Signaling 2 (SOCS-2)-Deficient Mice Is Dependent on Signal Transducer and Activator of Transcription 5b (STAT5b)

Molecular Endocrinology ◽

10.1210/mend.16.6.0845 ◽

2002 ◽

Vol 16 (6) ◽

pp. 1394-1406 ◽

Cited By ~ 76

Author(s):

Christopher J. Greenhalgh ◽

Patrick Bertolino ◽

Sylvia L. Asa ◽

Donald Metcalf ◽

Jason E. Corbin ◽

...

Keyword(s):

Postnatal Growth ◽

Cytokine Signaling ◽

Growth Enhancement ◽

Signal Transducer ◽

Primary Hepatocytes ◽

Suppressor Of Cytokine Signaling ◽

Embryonic Fibroblasts ◽

Adult Mice ◽

Igf I ◽

Deficient Mice

Abstract Mice lacking suppressor of cytokine signaling-2 (SOCS-2) exhibit accelerated postnatal growth resulting in adult mice that are 1.3 to 1.5 times the size of normal mice. In this study we examined the somatotrophic pathway to determine whether the production or actions of GH or IGF-I are altered in these mice. We demonstrated that SOCS-2−/− mice do not have elevated GH levels and suffer no major pituitary dysmorphogenesis, and that SOCS-2-deficient embryonic fibroblasts do not have altered IGF-I signaling. Primary hepatocytes from SOCS-2−/− mice, however, did have moderately prolonged signal transducer and activator of transcription 5 signaling in response to GH stimulation. Furthermore, the deletion of SOCS-2 from mice also lacking signal transducer and activator of transcription 5b had little effect on growth, suggesting that the action of SOCS-2 may be the regulation of the GH signaling pathway.

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Prolactin and the expression of suppressor of cytokine signaling-3 in the sheep adrenal gland before birth

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00252.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. R1399-R1405 ◽

Cited By ~ 4

Author(s):

S. Gentili ◽

J. S. Schwartz ◽

M. J. Waters ◽

I. C. McMillen

Keyword(s):

Adrenal Gland ◽

Mrna Expression ◽

Tissue Growth ◽

Late Gestation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Subsequent Increase ◽

Fetal Sheep

The fetal pituitary-adrenal axis plays a key role in the fetal response to intrauterine stress and in the timing of parturition. The fetal sheep adrenal gland is relatively refractory to stimulation in midgestation (90–120 days) before the prepartum activation, which occurs around 135 days gestation (term = 147 ± 3 days). The mechanisms underlying the switch from adrenal quiescence to activation are unclear. Therefore, we have investigated the expression of suppressor of cytokine signaling-3 (SOCS-3), a putative inhibitor of tissue growth in the fetal sheep adrenal between 50 and 145 days gestation and in the adrenal of the growth-restricted fetal sheep in late gestation. SOCS-3 is activated by a range of cytokines, including prolactin (PRL), and we have, therefore, determined whether PRL administered in vivo or in vitro stimulates SOCS-3 mRNA expression in the fetal adrenal in late gestation. There was a decrease ( P < 0.005) in SOCS-3 expression in the fetal adrenal between 54 and 133 days and between 141 and 144 days gestation. Infusion of the dopaminergic agonist, bromocriptine, which suppressed fetal PRL concentrations but did not decrease adrenal SOCS-3 mRNA expression. PRL administration, however, significantly increased adrenal SOCS-3 mRNA expression ( P < 0.05). Similarly, there was an increase ( P < 0.05) in SOCS-3 mRNA expression in adrenocortical cells in vitro after exposure to PRL (50 ng/ml). Placental and fetal growth restriction had no effect on SOCS-3 expression in the adrenal during late gestation. In summary, the decrease in the expression of the inhibitor SOCS-3 after 133 days gestation may be permissive for a subsequent increase in fetal adrenal growth before birth. We conclude that factors other than PRL act to maintain adrenal SOCS-3 mRNA expression before 133 days gestation but that acute elevations of PRL can act to upregulate adrenal SOCS-3 expression in the sheep fetus during late gestation.

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Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00652.2013 ◽

2014 ◽

Vol 307 (2) ◽

pp. E186-E198 ◽

Cited By ~ 23

Author(s):

Yueshui Zhao ◽

Xiaoqiu Xiao ◽

Stuart J. Frank ◽

Herbert Y. Lin ◽

Yin Xia

Keyword(s):

Growth Hormone ◽

Target Gene ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Gh Receptor ◽

Tnf Α ◽

Igf I ◽

Socs3 Expression ◽

Gh Resistance

During inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the GH target gene IGF-I and activation of catabolism. Proinflammatory cytokines IL-6, TNF-α, and IL-1β are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-α, and IL-1β to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-α and IL-1β inhibited GH receptor (GHR) expression but had minor effects on the downstream suppressor of cytokine signaling (SOCS)3, while IL-6 induced SOCS3 expression but had no effect on GHR expression in Huh-7 cells. Consistent with the in vitro observations, neutralization of TNF-α and IL-1β in mouse models of inflammation did not significantly alter SOCS3 expression stimulated by inflammation but restored GHR and IGF-I expression suppressed by inflammation. Neutralization of IL-6 did not alter inflammation-suppressed GHR expression but drastically reduced the inflammation-stimulated SOCS3 expression and restored IGF-I expression. Interestingly, when the GH-IGF-I pathway was turned off by maximal inhibition of GHR expression, IL-6 and SOCS3 were no longer able to regulate IGF-I expression. Taken together, our results suggest that TNF-α/IL-1β and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-α and IL-1β acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-α and IL-1β that inhibit GHR expression.

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miR-155 accelerates proliferation of mouse hepatocytes during liver regeneration by directly targeting SOCS1

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00072.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. G443-G453 ◽

Cited By ~ 7

Author(s):

Xia Lin ◽

Li Chen ◽

Haiyan Li ◽

Yu Liu ◽

Yanhong Guan ◽

...

Keyword(s):

Cell Cycle ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Molecular Mechanisms ◽

Pharmacological Intervention ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Proliferation Of Hepatocytes

Liver regeneration after two-thirds partial hepatectomy (PH) is a clinically significant repair process for restoring proper liver architecture. Although microRNA-155 (miR-155) has been found to serve as a crucial microRNA regulator that controls liver cell function and proliferation, little is known about its specific role in the regenerating liver. Using a mouse model with miR-155 overexpression or miR-155 knockout, we investigated the molecular mechanisms of miR-155 in liver regeneration. We found a marked induction of miR-155 in C57BL/6 mice after PH. Furthermore, RL-m155 mice showed enhanced liver regeneration as a result of accelerated progression of hepatocytes into the cell cycle, mainly through an increase in cyclin levels. However, proliferation of hepatocytes was delayed in miR-155-deficient livers. Expression of suppressor of cytokine signaling 1 (SOCS1) was dramatically downregulated in the process of liver regeneration, and enhancement of SOCS1 contributed to impaired proliferation of hepatocytes. Additionally, in vitro and in vivo experiments showed that adenovirus- or adeno-associated virus-mediated overexpression of SOCS1 attenuated improved liver regeneration induced by miR-155 overexpression. Our study shows that miR-155 is a pro-proliferative regulator in liver regeneration by facilitating the cell cycle and directly targeting SOCS1. NEW & NOTEWORTHY Our findings suggest a microRNA-155 (miR-155)-mediated positive regulation pattern in liver regeneration. A series of in vivo and in vitro studies showed that miR-155 upregulation enhanced partial hepatectomy-induced proliferation of hepatocytes by promoting the cell cycle without inducing DNA damage or apoptosis. Suppressor of cytokine signaling 1, a target gene of miR-155, antagonized the proliferation-promoting effect of miR-155. Therefore, pharmacological intervention targeting miR-155 may be therapeutically beneficial in various liver diseases.

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