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Synergistic effect of pro-inflammatory TNFα and IL-17 in periostin mediated collagen deposition: potential role in liver fibrosis.
Amara S, Lopez K, Banan B, Brown SK, Whalen M, Myles E, Ivy MT, Johnson T, Schey KL, Tiriveedhi V
(2015) Mol Immunol 64: 26-35
MeSH Terms: Cell Adhesion Molecules, Collagen Type I, DNA, Neoplasm, Fibroblasts, Hep G2 Cells, Humans, Inflammation Mediators, Interleukin-17, Liver Cirrhosis, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-jun, STAT3 Transcription Factor, Transcription, Genetic, Tumor Necrosis Factor-alpha
Show Abstract · Added February 12, 2015
BACKGROUND - The pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-17, have been implicated in the pathogenesis of liver fibrosis. In this study, we investigated the role of TNFα and IL-17 toward induction of profibrotic factor, periostin.
METHODS - HepG2 cells were cultured and treated with inflammatory cytokines, TNFα and IL-17. Computational promoter sequence analysis of the periostin promoter was performed to define the putative binding sites for transcription factors. Transcription factors were analyzed by Western blot and Chromatin Immunoprecipitation. Periostin and transcription factor expression analysis was performed by RT-PCR, Western blot, and fluorescence microscopy. Type I collagen expression from fibroblast cultures was analyzed by Western blot and Sircol soluble collagen assay.
RESULTS - Activation of HepG2 Cells with TNFα and IL-17 enhanced the expression of periostin (3.5 and 4.4 fold, respectively p<0.05) compared to untreated cells. However, combined treatment with both TNFα and IL-17 at similar concentration demonstrated a 13.3 fold increase in periostin (p<0.01), thus suggesting a synergistic role of these cytokines. Periostin promoter analysis and specific siRNA knock-down revealed that TNFα induces periostin through cJun, while IL-17 induced periostin via STAT-3 signaling mechanisms. Treatment of the supernatant from the cytokine activated HepG2 cells on fibroblast cultures induced enhanced expression of type I collagen (>9.1 fold, p<0.01), indicative of a direct fibrogenic effect of TNFα and IL-17.
CONCLUSION - TNFα and IL-17 induced fibrogenesis through cJun and STAT-3 mediated expression of profibrotic biomarker, periostin. Therefore, periostin might serve as a novel biomarker in early diagnosis of liver fibrosis.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer.
Zhang H, Yu C, Dai J, Keller JM, Hua A, Sottnik JL, Shelley G, Hall CL, Park SI, Yao Z, Zhang J, McCauley LK, Keller ET
(2014) Oncogene 33: 2464-77
MeSH Terms: Blotting, Western, Cell Line, Tumor, Chromatin Immunoprecipitation, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Intercellular Signaling Peptides and Proteins, Male, Parathyroid Hormone-Related Protein, Promoter Regions, Genetic, Prostatic Neoplasms, Proto-Oncogene Proteins c-jun, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added March 5, 2014
Prostate cancer (PCa)bone metastases are unique in that majority of them induce excessive mineralized bone matrix, through undefined mechanisms, as opposed to most other cancers that induce bone resorption. Parathyroid hormone-related protein (PTHrP) is produced by PCa cells and intermittent PTHrP exposure has bone anabolic effects, suggesting that PTHrP could contribute to the excess bone mineralization. Wnts are bone-productive factors produced by PCa cells, and the Wnt inhibitor Dickkopfs-1 (DKK1) has been shown to promote PCa progression. These findings, in conjunction with the observation that PTHrP expression increases and DKK1 expression decreases as PCa progresses, led to the hypothesis that PTHrP could be a negative regulator of DKK1 expression in PCa cells and, hence, allow the osteoblastic activity of Wnts to be realized. To test this, we first demonstrated that PTHrP downregulated DKK1 mRNA and protein expression. We then found through multiple mutated DKK1 promoter assays that PTHrP, through c-Jun activation, downregulated the DKK1 promoter through a transcription factor (TCF) response element site. Furthermore, chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that PTHrP mediated this effect through inducing c-Jun to bind to a transcriptional activator complex consisting of β-catenin, which binds the most proximal DKK1 promoter, the TCF response element. Together, these results demonstrate a novel signaling linkage between PTHrP and Wnt signaling pathways that results in downregulation of a Wnt inhibitor allowing for Wnt activity that could contribute the osteoblastic nature of PCa.
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16 MeSH Terms
Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages.
Asim M, Chaturvedi R, Hoge S, Lewis ND, Singh K, Barry DP, Algood HS, de Sablet T, Gobert AP, Wilson KT
(2010) J Biol Chem 285: 20343-57
MeSH Terms: Animals, Anthracenes, Apoptosis, Cell Line, Cell Nucleus, Cell Survival, Extracellular Signal-Regulated MAP Kinases, Flavonoids, Fluorescence Resonance Energy Transfer, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Imidazoles, Immunoblotting, Macromolecular Substances, Macrophages, Mice, Mice, Inbred C57BL, Ornithine Decarboxylase, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Pyridines, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor AP-1
Show Abstract · Added March 5, 2014
Macrophages are essential components of innate immunity, and apoptosis of these cells impairs mucosal defense to microbes. Helicobacter pylori is a gastric pathogen that infects half of the world population and causes peptic ulcer disease and gastric cancer. The host inflammatory response fails to eradicate the organism. We have reported that H. pylori induces apoptosis of macrophages by generation of polyamines from ornithine decarboxylase (ODC), which is dependent on c-Myc as a transcriptional enhancer. We have now demonstrated that expression of c-Myc requires phosphorylation and nuclear translocation of ERK, which results in phosphorylation of c-Fos and formation of a specific activator protein (AP)-1 complex. Electromobility shift assay and immunoprecipitation revealed a previously unrecognized complex of phospho-c-Fos (pc-Fos) and c-Jun in the nucleus. Fluorescence resonance energy transfer demonstrated the interaction of pc-Fos and c-Jun. The capacity of this AP-1 complex to bind to putative AP-1 sequences was demonstrated by oligonucleotide pulldown and fluorescence polarization. Binding of the pc-Fos.c-Jun complex to the c-Myc promoter was demonstrated by chromatin immunoprecipitation. A dominant-negative c-Fos inhibited H. pylori-induced expression of c-Myc and ODC and apoptosis. H. pylori infection of mice induced a rapid infiltration of macrophages into the stomach. Concomitant apoptosis depleted these cells, and this was associated with formation of a pc-Fos.c-Jun complex. Treatment of mice with an inhibitor of ERK phosphorylation attenuated phosphorylation of c-Fos, expression of ODC, and apoptosis in gastric macrophages. A unique AP-1 complex in gastric macrophages contributes to the immune escape of H. pylori.
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26 MeSH Terms
Analysis of SRrp86-regulated alternative splicing: control of c-Jun and IκBβ activity.
Solis AS, Patton JG
(2010) RNA Biol 7: 486-94
MeSH Terms: Alternative Splicing, Animals, Cell Line, Tumor, HeLa Cells, Humans, I-kappa B Proteins, Microarray Analysis, NF-kappa B, Nuclear Proteins, Proto-Oncogene Proteins c-jun, RNA Splicing, RNA-Binding Proteins, Rats, Serine-Arginine Splicing Factors
Show Abstract · Added May 27, 2014
Previous work led to the hypothesis that SRrp86, a related member of the SR protein superfamily, can interact with and modulate the activity of other SR proteins. Here, we sought to test this hypothesis by examining the effect of changing SRrp86 concentrations on overall alternative splicing patterns. SpliceArrays were used to examine 9,854 splicing events in wild-type cells, cells overexpressing SRrp86, and cells treated with siRNAs to knockdown SRrp86. From among the 500 splicing events exhibiting altered splicing under these conditions, the splicing of c-Jun and IκBβ were validated as being regulated by SRrp86 resulting in altered regulation of their downstream targets. In both cases, functionally distinct isoforms were generated that demonstrate the role SRrp86 plays in controlling alternative splicing.
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14 MeSH Terms
Quantitative AP-1 gene regulation by oxidative stress in the human retinal pigment epithelium.
Chaum E, Yin J, Yang H, Thomas F, Lang JC
(2009) J Cell Biochem 108: 1280-91
MeSH Terms: Cell Line, Gene Expression Regulation, Humans, Oxidative Stress, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Retinal Pigment Epithelium, Transcription Factor AP-1, Transcriptional Activation
Show Abstract · Added June 11, 2018
The purpose of this study was to characterize the early molecular responses to quantified levels of oxidative stress (OS) in the human retinal pigment epithelium (RPE). Confluent ARPE-19 cells were cultured for 3 days in defined medium to stabilize gene expression. The cells were exposed to varying levels of OS (0-500 microM H(2)O(2)) for 1-8 h and gene expression was followed for up to 24-h after OS. Using real-time qPCR, we quantified the expression of immediate early genes from the AP-1 transcription factor family and other genes involved in regulating the redox status of the cells. Significant and quantitative changes were seen in the expression of six AP-1 transcription factor genes, FosB, c-Fos, Fra-1, c-Jun, JunB, and ATF3 from 1-8 h following OS. The peak level of induced transcription from OS varied from 2- to 128-fold over the first 4 h, depending on the gene and magnitude of OS. Increased transcription at higher levels of OS was also seen for up to 8-h for some of these genes. Protein translation was examined for 24-h following OS using Western blotting methods, and compared to the qPCR responses. We identified six AP-1 family genes that demonstrate quantitative upregulation of expression in response to OS. Two distinct types of quantifiable OS-specific responses were observed; dose-dependent responses, and threshold responses. Our studies show that different levels of OS can regulate the expression of AP-1 transcription factors quantitatively in the human RPE in vitro.
(c) 2009 Wiley-Liss, Inc.
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MeSH Terms
Lipopolysaccharide-dependent interaction between PU.1 and c-Jun determines production of lipocalin-type prostaglandin D synthase and prostaglandin D2 in macrophages.
Joo M, Kwon M, Cho YJ, Hu N, Pedchenko TV, Sadikot RT, Blackwell TS, Christman JW
(2009) Am J Physiol Lung Cell Mol Physiol 296: L771-9
MeSH Terms: Animals, Base Sequence, Binding Sites, Cell Line, Female, Humans, Intramolecular Oxidoreductases, JNK Mitogen-Activated Protein Kinases, Lipocalins, Lipopolysaccharides, Macrophages, Male, Mice, Mice, Inbred C57BL, Models, Biological, Molecular Sequence Data, Promoter Regions, Genetic, Prostaglandin D2, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Trans-Activators, Transcriptional Activation, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 5, 2014
Previously, we reported that expression of lipocalin-prostaglandin D synthase (L-PGDS) is inducible in macrophages and protects from Pseudomonas pneumonia. Here, we investigated the mechanism by which L-PGDS gene expression is induced in macrophages. A promoter analysis of the murine L-PGDS promoter located a binding site of PU.1, a transcription factor essential for macrophage development and inflammatory gene expression. A chromatin immunoprecipitation assay showed that PU.1 bound to the cognate site in the endogenous L-PGDS promoter in response to LPS. Overexpression of PU.1, but not of PU.1(S148A), a mutant inert to casein kinase II (CKII) or NF-kappaB-inducing kinase (NIK), induced L-PGDS in RAW 264.7 cells. Conversely, siRNA silencing of PU.1 expression blunted productions of L-PGDS and prostaglandin D2 (PGD(2)). LPS treatment induced formation of the complex of PU.1 and cJun on the PU.1 site, but inactivation of cJun by treatment with JNK or p38 kinase inhibitor abolished the complex, and suppressed PU.1 transcriptional activity for L-PGDS gene expression. Together, these results show that PU.1, activated by CKII or NIK, cooperates with MAPK-activated cJun to maximally induce L-PGDS expression in macrophages following LPS treatment, and suggest that PU.1 participates in innate immunity through the production of L-PGDS and PGD(2).
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24 MeSH Terms
The role of proline-rich protein tyrosine kinase 2 in differentiation-dependent signaling in human epidermal keratinocytes.
Schindler EM, Baumgartner M, Gribben EM, Li L, Efimova T
(2007) J Invest Dermatol 127: 1094-106
MeSH Terms: Calcium, Cell Differentiation, Cell Nucleus, Cells, Cultured, Epidermal Cells, Epidermis, Focal Adhesion Kinase 2, Gene Expression Regulation, Humans, Indoles, Keratinocytes, Maleimides, Protein Kinase C, Protein Precursors, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Signal Transduction, Tetradecanoylphorbol Acetate
Show Abstract · Added May 30, 2013
Non-receptor tyrosine kinase proline-rich protein tyrosine kinase 2 (Pyk2) functions as an integrator of multiple signaling pathways involved in the regulation of fundamental cellular processes. Pyk2 expression, regulation, and functions in skin have not been examined. Here we investigated the expression and subcellular localization of Pyk2 in human epidermis and in primary human keratinocytes, and studied the mechanisms of Pyk2 activation by differentiation-inducing stimuli, and the role of Pyk2 as a regulator of keratinocyte differentiation. We demonstrate that Pyk2 is abundantly expressed in skin keratinocytes. Notably, the endogenous Pyk2 protein is predominantly localized in keratinocyte nuclei throughout all layers of healthy human epidermis, and in cultured human keratinocytes. Pyk2 is activated by treatment with keratinocyte-differentiating agents, 12-O-tetradecanoylphorbol-13-acetate and calcium via a mechanism that requires intracellular calcium release and functional protein kinase C (PKC) and Src activities. Particularly, differentiation-promoting PKC delta and PKC eta elicit Pyk2 activation. Our data show that Pyk2 increases promoter activity and endogenous protein levels of involucrin, a marker of keratinocyte terminal differentiation. This regulation is associated with increased expression of Fra-1 and JunD, activator protein-1 transcription factors known to be required for involucrin expression. Altogether, these results provide insights into Pyk2 signaling in epidermis and reveal a novel role for Pyk2 in regulation of keratinocyte differentiation.
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18 MeSH Terms
Interleukin-6 protects retinal ganglion cells from pressure-induced death.
Sappington RM, Chan M, Calkins DJ
(2006) Invest Ophthalmol Vis Sci 47: 2932-42
MeSH Terms: Animals, Animals, Newborn, Apoptosis, Astrocytes, Cell Separation, Cytoprotection, Enzyme-Linked Immunosorbent Assay, Hydrostatic Pressure, Immunohistochemistry, In Situ Nick-End Labeling, Interleukin-6, Microglia, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-jun, RNA, Messenger, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Retinal Ganglion Cells, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, bcl-2-Associated X Protein
Show Abstract · Added May 27, 2014
PURPOSE - The response of retinal ganglion cells (RGCs) to ocular pressure in glaucoma likely involves signals from astrocytes and microglia. How glia-derived factors influence RGC survival at ambient and elevated pressure and whether the inflammatory cytokine interleukin-6 (IL-6) is a contributing factor were investigated.
METHODS - Primary cultures of retinal astrocytes, microglia, and RGCs were prepared using immunomagnetic separation. Comparisons were made of RGC survival at ambient and elevated pressure (+70 mm Hg) and with pressure-conditioned medium from glia with, and depleted of, IL-6.
RESULTS - Pressure elevated for 24 to 48 hours reduced RGC density, increased TUNEL labeling, and upregulated several apoptotic genes, including the early immediate genes c-jun and jun-B. Pressure-conditioned medium from astrocytes reduced RGC survival another 38%, while microglia medium returned RGC survival to ambient levels. These effects were unrelated to IL-6 in microglia medium. Neither astrocyte- nor microglia-conditioned medium affected ambient RGC survival unless depleted of IL-6, which induced a 63% and a 18% decrease in RGCs, respectively. Recombinant IL-6 equivalent to levels in glia-conditioned medium doubled RGC survival at elevated pressure.
CONCLUSIONS - For RGCs at ambient pressure, IL-6 secreted from astrocytes and microglia under pressure is adequate to abate other proapoptotic signals from these glia. For RGCs challenged by elevated pressure, decreased IL-6 in astrocyte medium is insufficient to counteract these signals. Increased IL-6 in microglia medium counters not only proapoptotic signals from these cells but also the pressure-induced apoptotic cascade intrinsic to RGCs.
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22 MeSH Terms
Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.
Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG, Schlisio S
(2005) Cancer Cell 8: 155-67
MeSH Terms: Adrenal Gland Neoplasms, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, DNA-Binding Proteins, Dioxygenases, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Immediate-Early Proteins, Mutation, Nerve Growth Factor, Neurons, Pheochromocytoma, Procollagen-Proline Dioxygenase, Protein Kinase C, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Signal Transduction, Succinate Dehydrogenase, Sympathetic Nervous System, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added March 5, 2014
Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EglN3 acts downstream of c-Jun and is specifically required among the three EglN family members for apoptosis in this setting. Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.
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26 MeSH Terms
c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation.
Palmada M, Kanwal S, Rutkoski NJ, Gustafson-Brown C, Johnson RS, Wisdom R, Carter BD, Gufstafson-Brown C
(2002) J Cell Biol 158: 453-61
MeSH Terms: Animals, Apoptosis, Base Sequence, Brain-Derived Neurotrophic Factor, Cells, Cultured, Cycloheximide, Gene Expression Regulation, Developmental, Genetic Vectors, Green Fluorescent Proteins, Immunohistochemistry, Indicators and Reagents, Integrases, Luminescent Proteins, Mice, Mice, Knockout, Mutation, Nerve Growth Factor, Neurons, Protein Synthesis Inhibitors, Proto-Oncogene Proteins c-jun, Receptor, Nerve Growth Factor, Superior Cervical Ganglion, Transfection, Viral Proteins
Show Abstract · Added March 5, 2014
Sympathetic neurons depend on NGF binding to TrkA for their survival during vertebrate development. NGF deprivation initiates a transcription-dependent apoptotic response, which is suggested to require activation of the transcription factor c-Jun. Similarly, apoptosis can also be induced by selective activation of the p75 neurotrophin receptor. The transcriptional dependency of p75-mediated cell death has not been determined; however, c-Jun NH2-terminal kinase has been implicated as an essential component. Because the c-jun-null mutation is early embryonic lethal, thereby hindering a genetic analysis, we used the Cre-lox system to conditionally delete this gene. Sympathetic neurons isolated from postnatal day 1 c-jun-floxed mice were infected with an adenovirus expressing Cre recombinase or GFP and analyzed for their dependence on NGF for survival. Cre immunopositive neurons survived NGF withdrawal, whereas those expressing GFP or those uninfected underwent apoptosis within 48 h, as determined by DAPI staining. In contrast, brain-derived neurotrophic factor (BDNF) binding to p75 resulted in an equivalent level of apoptosis in neurons expressing Cre, GFP, and uninfected cells. Nevertheless, cycloheximide treatment prevented BDNF-mediated apoptosis. These results indicate that whereas c-jun is required for apoptosis in sympathetic neurons on NGF withdrawal, an alternate signaling pathway must be induced on p75 activation.
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24 MeSH Terms