Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 11

Publication Record

Connections

Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/β-catenin signaling.
Ahmad R, Kumar B, Chen Z, Chen X, Müller D, Lele SM, Washington MK, Batra SK, Dhawan P, Singh AB
(2017) Oncogene 36: 6592-6604
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Cell Transformation, Neoplastic, Claudin-3, Colon, Colonic Neoplasms, Colorectal Neoplasms, Cytokine Receptor gp130, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, Intestinal Mucosa, Mice, Mice, Knockout, Permeability, STAT3 Transcription Factor, Up-Regulation, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added March 14, 2018
The hyperactivated Wnt/β-catenin signaling acts as a switch to induce epithelial to mesenchymal transition and promote colorectal cancer. However, due to its essential role in gut homeostasis, therapeutic targeting of this pathway has proven challenging. Additionally, IL-6/Stat-3 signaling, activated by microbial translocation through the dysregulated mucosal barrier in colon adenomas, facilitates the adenoma to adenocarcinomas transition. However, inter-dependence between these signaling pathways and key mucosal barrier components in regulating colon tumorigenesis and cancer progression remains unclear. In current study, we have discovered, using a comprehensive investigative regimen, a novel and tissue-specific role of claudin-3, a tight junction integral protein, in inhibiting colon cancer progression by serving as the common rheostat of Stat-3 and Wnt-signaling activation. Loss of claudin-3 also predicted poor patient survival. These findings however contrasted an upregulated claudin-3 expression in other cancer types and implicated role of the epigenetic regulation. Claudin-3-/- mice revealed dedifferentiated and leaky colonic epithelium, and developed invasive adenocarcinoma when subjected to colon cancer. Wnt-signaling hyperactivation, albeit in GSK-3β independent manner, differentiated colon cancer in claudin-3-/- mice versus WT-mice. Claudin-3 loss also upregulated the gp130/IL6/Stat3 signaling in colonic epithelium potentially assisted by infiltrating immune components. Genetic and pharmacological studies confirmed that claudin-3 loss induces Wnt/β-catenin activation, which is further exacerbated by Stat-3-activation and help promote colon cancer. Overall, these novel findings identify claudin-3 as a therapeutic target for inhibiting overactivation of Wnt-signaling to prevent CRC malignancy.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass.
Walker EC, Johnson RW, Hu Y, Brennan HJ, Poulton IJ, Zhang JG, Jenkins BJ, Smyth GK, Nicola NA, Sims NA
(2016) J Biol Chem 291: 21703-21716
MeSH Terms: Animals, Bone Diseases, Metabolic, Bone and Bones, Cytokine Receptor gp130, Disease Models, Animal, Humans, Leukemia Inhibitory Factor Receptor alpha Subunit, Mice, Oncostatin M, Oncostatin M Receptor beta Subunit, Organ Size, Osteocytes, Phosphorylation, STAT1 Transcription Factor, STAT3 Transcription Factor
Show Abstract · Added March 26, 2019
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are IL-6 family members with a wide range of biological functions. Human OSM (hOSM) and murine LIF (mLIF) act in mouse cells via a LIF receptor (LIFR)-glycoprotein 130 (gp130) heterodimer. In contrast, murine OSM (mOSM) signals mainly via an OSM receptor (OSMR)-gp130 heterodimer and binds with only very low affinity to mLIFR. hOSM and mLIF stimulate bone remodeling by both reducing osteocytic sclerostin and up-regulating the pro-osteoclastic factor receptor activator of NF-κB ligand (RANKL) in osteoblasts. In the absence of OSMR, mOSM still strongly suppressed sclerostin and stimulated bone formation but did not induce RANKL, suggesting that intracellular signaling activated by the low affinity interaction of mOSM with mLIFR is different from the downstream effects when mLIF or hOSM interacts with the same receptor. Both STAT1 and STAT3 were activated by mOSM in wild type cells or by mLIF/hOSM in wild type and Osmr cells. In contrast, in Osmr primary osteocyte-like cells stimulated with mOSM (therefore acting through mLIFR), microarray expression profiling and Western blotting analysis identified preferential phosphorylation of STAT3 and induction of its target genes but not of STAT1 and its target genes; this correlated with reduced phosphorylation of both gp130 and LIFR. In a mouse model of spontaneous osteopenia caused by hyperactivation of STAT1/3 signaling downstream of gp130 (gp130), STAT1 deletion rescued the osteopenic phenotype, indicating a beneficial effect of promoting STAT3 signaling over STAT1 downstream of gp130 in this low bone mass condition, and this may have therapeutic value.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone.
Johnson RW, McGregor NE, Brennan HJ, Crimeen-Irwin B, Poulton IJ, Martin TJ, Sims NA
(2015) Bone 81: 343-351
MeSH Terms: Animals, Bone Marrow, Bone Marrow Cells, Bone and Bones, Cartilage, Cathepsin K, Cytokine Receptor gp130, Female, Femur, Gene Deletion, Interleukin-6, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoclasts, Osteogenesis, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-11, Receptors, Interleukin-6, Sex Factors, Signal Transduction, X-Ray Microtomography
Show Abstract · Added March 26, 2019
Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signalling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labelled surface and mineral apposition rate. By 26 weeks of age, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL-6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were also reduced in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity through the stimulation of osteoclast-derived "coupling factors" and "osteotransmitters", respectively.
Copyright © 2015 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
MeSH Terms
Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-κB/interleukin-6 (IL-6) axis in mouse mammary cells.
Guyer RA, Macara IG
(2015) J Biol Chem 290: 8457-68
MeSH Terms: Animals, Autocrine Communication, Cell Adhesion Molecules, Cells, Cultured, Cytokine Receptor gp130, Enzyme Activation, Epithelial Cells, Female, Interleukin-6, Mammary Glands, Animal, Mice, Inbred C3H, NF-kappa B, Phosphorylation, Protein Kinase C, Protein Processing, Post-Translational, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added April 10, 2018
PAR3 suppresses tumor growth and metastasis in vivo and cell invasion through matrix in vitro. We propose that PAR3 organizes and limits multiple signaling pathways and that inappropriate activation of these pathways occurs without PAR3. Silencing Pard3 in conjunction with oncogenic activation promotes invasion and metastasis via constitutive STAT3 activity in mouse models, but the mechanism for this is unknown. We now show that loss of PAR3 triggers increased production of interleukin-6, which induces STAT3 signaling in an autocrine manner. Activation of atypical protein kinase C ι/λ (aPKCι/λ) mediates this effect by stimulating NF-κB signaling and IL-6 expression. Our results suggest that PAR3 restrains aPKCι/λ activity and thus prevents aPKCι/λ from activating an oncogenic signaling network.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
gp130 in late osteoblasts and osteocytes is required for PTH-induced osteoblast differentiation.
Standal T, Johnson RW, McGregor NE, Poulton IJ, Ho PW, Martin TJ, Sims NA
(2014) J Endocrinol 223: 181-90
MeSH Terms: Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Cytokine Receptor gp130, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoblasts, Osteocytes, Osteogenesis, Parathyroid Hormone, Receptor, Parathyroid Hormone, Type 1
Show Abstract · Added March 26, 2019
Parathyroid hormone (PTH) treatment stimulates osteoblast differentiation and bone formation, and is the only currently approved anabolic therapy for osteoporosis. In cells of the osteoblast lineage, PTH also stimulates the expression of members of the interleukin 6 (IL-6) cytokine superfamily. Although the similarity of gene targets regulated by these cytokines and PTH suggest cooperative action, the dependence of PTH anabolic action on IL-6 cytokine signaling is unknown. To determine whether cytokine signaling in the osteocyte through glycoprotein 130 (gp130), the common IL-6 superfamily receptor subunit, is required for PTH anabolic action, male mice with conditional gp130 deletion in osteocytes (Dmp1Cre.gp130(f/f)) and littermate controls (Dmp1Cre.gp130(w/w)) were treated with hPTH(1-34) (30 μg/kg 5× per week for 5 weeks). PTH dramatically increased bone formation in Dmp1Cre.gp130(w/w) mice, as indicated by elevated osteoblast number, osteoid surface, mineralizing surface, and increased serum N-terminal propeptide of type 1 collagen (P1NP). However, in mice with Dmp1Cre-directed deletion of gp130, PTH treatment changed none of these parameters. Impaired PTH anabolic action was associated with a 50% reduction in Pth1r mRNA levels in Dmp1Cre.gp130(f/f) femora compared with Dmp1Cre.gp130(w/w). Furthermore, lentiviral-Cre infection of gp130(f/f) primary osteoblasts also lowered Pth1r mRNA levels to 16% of that observed in infected C57/BL6 cells. In conclusion, osteocytic gp130 is required to maintain PTH1R expression in the osteoblast lineage, and for the stimulation of osteoblast differentiation that occurs in response to PTH.
© 2014 Society for Endocrinology.
0 Communities
1 Members
0 Resources
MeSH Terms
SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation.
Robson MJ, Turner RC, Naser ZJ, McCurdy CR, O'Callaghan JP, Huber JD, Matsumoto RR
(2014) Exp Neurol 254: 180-9
MeSH Terms: Animals, Astrocytes, Benzoxazoles, Central Nervous System Stimulants, Corpus Striatum, Cytokine Receptor gp130, Dopaminergic Neurons, Drug Interactions, Fever, Glial Fibrillary Acidic Protein, Gliosis, Male, Methamphetamine, Mice, Oncostatin M Receptor beta Subunit, Phosphorylation, Piperazines, Receptors, sigma, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added August 26, 2015
Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.
Copyright © 2014 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
20 MeSH Terms
The primary function of gp130 signaling in osteoblasts is to maintain bone formation and strength, rather than promote osteoclast formation.
Johnson RW, Brennan HJ, Vrahnas C, Poulton IJ, McGregor NE, Standal T, Walker EC, Koh TT, Nguyen H, Walsh NC, Forwood MR, Martin TJ, Sims NA
(2014) J Bone Miner Res 29: 1492-505
MeSH Terms: Animals, Bone and Bones, Cell Count, Cell Lineage, Collagen Type I, Cytokine Receptor gp130, Female, Gene Deletion, Gene Knockdown Techniques, Glycoproteins, Integrases, Male, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Organ Size, Osteoblasts, Osteocalcin, Osteoclasts, Osteocytes, Osteogenesis, Reproducibility of Results, Signal Transduction, Sp7 Transcription Factor, Transcription Factors
Show Abstract · Added March 26, 2019
Interleukin-6 (IL-6) family cytokines act via gp130 in the osteoblast lineage to stimulate the formation of osteoclasts (bone resorbing cells) and the activity of osteoblasts (bone forming cells), and to inhibit expression of the osteocyte protein, sclerostin. We report here that a profound reduction in trabecular bone mass occurs both when gp130 is deleted in the entire osteoblast lineage (Osx1Cre gp130 f/f) and when this deletion is restricted to osteocytes (DMP1Cre gp130 f/f). This was caused not by an alteration in osteoclastogenesis, but by a low level of bone formation specific to the trabecular compartment. In contrast, cortical diameter increased to maintain ultimate bone strength, despite a reduction in collagen type 1 production. We conclude that osteocytic gp130 signaling is required for normal trabecular bone mass and proper cortical bone composition.
© 2014 American Society for Bone and Mineral Research.
0 Communities
1 Members
0 Resources
MeSH Terms
Leukemia inhibitory factor: a paracrine mediator of bone metabolism.
Sims NA, Johnson RW
(2012) Growth Factors 30: 76-87
MeSH Terms: Animals, Bone Diseases, Bone and Bones, Chondrocytes, Cytokine Receptor gp130, Gene Expression Regulation, Humans, Inflammation, Leukemia Inhibitory Factor, Leukemia Inhibitory Factor Receptor alpha Subunit, Mice, Osteoblasts, Osteogenesis
Show Abstract · Added March 26, 2019
Leukemia inhibitory factor (LIF) is a soluble interleukin-6 family cytokine that regulates a number of physiologic functions, including normal skeletal remodeling. LIF signals through the cytokine co-receptor glycoprotein-130 in complex with its cytokine-specific receptor [LIF receptor (LIFR)] to activate signaling cascades in cells of the skeletal system, including stromal cells, chondrocytes, osteoblasts, osteocytes, adipocytes, and synovial fibroblasts. LIF action on skeletal cells is cell-type specific, and frequently dependent on the state of cell differentiation. This review describes the expression patterns of LIF and LIFR in bone, their regulation by physiological and inflammatory agents, as well as cell-specific influences of LIF on osteoblast, osteoclast, chondrocyte, and adipocyte differentiation. The actions of LIF in normal skeletal growth and maintenance, in pathological states (e.g. autocrine tumor cell signaling and growth in bone) and inflammatory conditions (e.g. arthritis) will be discussed, as well as the signaling pathways activated by LIF and their importance in bone formation and resorption.
0 Communities
1 Members
0 Resources
MeSH Terms
Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth.
Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM, Eyler CE, Elderbroom J, Gallagher J, Schuschu J, MacSwords J, Cao Y, McLendon RE, Wang XF, Hjelmeland AB, Rich JN
(2009) Stem Cells 27: 2393-404
MeSH Terms: Animals, Apoptosis, Brain Neoplasms, Cell Proliferation, Cell Survival, Cytokine Receptor gp130, Glioma, Graft Survival, Growth Inhibitors, Humans, Interleukin-6, Mice, Mice, Nude, Neoplastic Stem Cells, RNA Interference, RNA, Small Interfering, Receptors, Interleukin-6, STAT3 Transcription Factor, Signal Transduction, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
Glioblastomas are the most common and most lethal primary brain tumor. Recent studies implicate an important role for a restricted population of neoplastic cells (glioma stem cells (GSCs)) in glioma maintenance and recurrence. We now demonstrate that GSCs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6R alpha) and glycoprotein 130 (gp130). Targeting IL6R alpha or IL6 ligand expression in GSCs with the use of short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription three (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis. These data indicate that STAT3 is a downstream mediator of prosurvival IL6 signals in GSCs. Targeting of IL6R alpha or IL6 expression in GSCs increases the survival of mice bearing intracranial human glioma xenografts. IL6 is clinically significant because elevated IL6 ligand and receptor expression are associated with poor glioma patient survival. The potential utility of anti-IL6 therapies is demonstrated by decreased growth of subcutaneous human GSC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for glioma patients.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo.
Bronte-Tinkew DM, Terebiznik M, Franco A, Ang M, Ahn D, Mimuro H, Sasakawa C, Ropeleski MJ, Peek RM, Jones NL
(2009) Cancer Res 69: 632-9
MeSH Terms: Adenocarcinoma, Animals, Antigens, Bacterial, Bacterial Proteins, Cell Line, Tumor, Cell Nucleus, Cytokine Receptor gp130, Gerbillinae, HeLa Cells, Helicobacter Infections, Helicobacter pylori, Humans, Male, Phosphorylation, Receptors, Interleukin-6, STAT3 Transcription Factor, Stomach Neoplasms, Transcription, Genetic, Tyrosine
Show Abstract · Added March 5, 2014
Persistent infection with Helicobacter pylori confers an increased risk for the development of gastric cancer. However, the exact mechanisms whereby this bacterium causes carcinogenesis have not been completely elucidated. Recent evidence indicates that aberrant activation of the signal transducers and activators of transcription 3 (STAT3) signaling pathway may play a role in gastric carcinogenesis. Therefore, we hypothesized that H. pylori infection modulates STAT3 signaling, favoring gastric cancer development. In epithelial cells infected with H. pylori, STAT3 was activated, as assessed by immunoblotting for phosphorylated STAT3, immunofluorescence of translocated STAT3, fluorescence recovery after photobleaching, and luciferase activation in transfected cells. Activation was dependent on translocation but not phosphorylation of cytotoxin-associated gene A (CagA) in host cells. Activation seemed to be receptor-mediated because preincubation of cells with the interleukin-6 (IL-6) receptor superantagonist sant7 or inhibition of gp130 by a monoclonal antibody prevented H. pylori-mediated STAT3 activation. However, activation was not related to autocrine activation by IL-6 or IL-11. CagA+ wild-type H. pylori, but not the noncarcinogenic cagA- mutant, activated STAT3 in gastric epithelial cells in vivo in the gerbil model of H. pylori-mediated gastric carcinogenesis. Collectively, these results indicate that H. pylori CagA activates the STAT3 signaling pathway in vitro and in vivo, providing a potential mechanism by which chronic H. pylori infection promotes the development of gastric cancer.
0 Communities
1 Members
0 Resources
19 MeSH Terms