Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration ...
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration ...
Cerebral ischemia is associated with the activation of glial cells, infiltration of leukocytes and an increase in inflammatory mediators in the ischemic brain and systemic circulation. How this inflammatory response influences lesion size and neurological outcome remains unclear. D-JNKI1, an inhibitor of the c-Jun N-terminal kinase pathway, is strongly neuroprotective in animal models of stroke. Intriguingly, the protection mediated by D-JNKI1 is high even with intravenous administration at very low doses with undetectable drug levels in the brain, pointing to a systemic mode of action, perhaps on inflammation. We evaluated whether D-JNKI1, administered intravenously 3 h after the onset of middle cerebral artery occlusion (MCAO), modulates secretion of the inflammatory mediators interleukin-6 and keratinocyte-derived chemokine in the plasma and from the spleen and brain at several time points after MCAO. We found an early release of both mediators in the systemic circulation followed by an increase in
MAPK8 [ENSP00000378974]. Stress-activated protein kinase JNK1; Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including ...
The structure-based design and synthesis of a novel series of c-Jun N-terminal kinase (JNK) inhibitors with selectivity against p38 is reported. The unique structure of 3,5-disubstituted quinolines (2) was developed from the previously reported 4-(2,7-phenanthrolin-9-yl)phenol (1). The X-ray crystal structure of 16a in JNK3 reveals an unexpected binding mode for this new scaffold with protein ...
Background: Alzheimers Disease (AD) is a neuron related brain disorder leading to reasoning and memory loss. There is no specific cure identified for AD. JNK3 (c-Jun N-terminal kinase /stress-activated protein kinase) are highly revealed within the central nervous system, particularly neurons, playing vital role in functioning of brain. JNK3 hyper phosphorylation is a very common conclusion in neurodegenerative diseases. JNK3 in turn hyper phosphorylates Amyloid Precursor Protein (APP) which leads to the formation of Amyloid β peptides (an inductive agent of Alzheimers disease). Methods: Protein JNK-3 (PDB ID: 3KVX) was retrieved from protein data bank and later we docked a library of compounds against it. These were further validated by ADMET studies. Results: Thus, docking inhibitors of JNK3 may provide a promising sanitive approach. Based on best docking score and glide score a potential lead is identified against JNK3. Conclusion: Inhibiting JNK-3 may lead to less production of amyloidβ ...
As well as providing a structural framework, the actin cytoskeleton plays integral roles in cell death, survival, and proliferation. The disruption of the actin cytoskeleton results in the activation of the c-Jun N-terminal kinase (JNK) stress-activated protein kinase (SAPK) pathway; however, the
Ursolic acid (UA), a pentacyclic triterpenoid, is known to have anti-tumor activity in various cancers including human non small cell lung cancer (NSCLC). However, the molecular mechanisms underlying the action of UA remain largely unknown. Cell viability was measured by MTT assays. Apoptosis was analyzed with Annexin V-FITC/PI Apoptosis Detection Kit by Flow cytometry. Western blot analysis was performed to measure the phosphorylation and protein expression of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), DNMT1 [DNA (cytosine-5)-methyltransferase 1], enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and SP1. Exogenous expression of SP1 and DNMT1 was carried out by transient transfection assays. We showed that UA inhibited the growth and induced apoptosis of NSCLC cells in the dose- and time-dependent fashion. Furthermore, we found that UA induced phosphorylation of SAPK/JNK and suppressed the protein expression of DNMT1 and EZH2. The inhibitor of SAPK/JNK (SP600125)
MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Requirement of the JIP1 scaffold protein for stress-induced JNK activation
MK08_HUMAN] Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In ...
Although accumulating evidence supports that JNK activation is involved in cancer development and progression [37, 38], the biological significance of JNK in gastric cancer remains unclear. The present study showed that constitutive activation of JNK was associated with specific clinicopathological factors, including pTNM stages, lymphatic invasion, and a better prognosis. We believe that this is the first report regarding the clinical implications of JNK in human gastric cancer. Furthermore, we found that JNK negatively regulates FOXO1 activation in gastric cancer cells. This finding contrasts with the results of the previous studies [22, 27-31], which showed JNK-induced activation of FOXO proteins in human cancer cells.. In the present study, JNK activation (evaluated by pJNK staining) was mainly observed in the proliferative zone of the gastric gland and in the areas showing intestinal metaplasia, which is known to be a predictor of gastric neoplasia [39], in the non-neoplastic gastric ...
Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. We observed that IL-6 increased IRS-1 phosphorylation at Ser312 and Ser616; these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr612, a site essential for engaging PI3-kinase. Furthermore, IL-6 ...
The stress-induced kinase, c-Jun-N-terminal kinase 1 (JNK1) has previously been implicated in the pathogenesis of lung fibrosis. However, the exact cell type(s) wherein JNK1 exerts its pro-fibrotic role(s) remained enigmatic. Herein we demonstrate prominent activation of JNK in bronchial epithelia using the mouse models of bleomycin- or AdTGFbeta1-induced fibrosis. Furthermore, in lung tissues of patients with idiopathic pulmonary fibrosis (IPF), active JNK was observed in various regions including type I and type II pneumocytes and fibroblasts. No JNK activity was observed in adjacent normal tissue or in normal control tissue. To address the role of epithelial JNK1, we ablated Jnk1 form bronchiolar and alveolar type II epithelial cells using CCSP-directed Cre recombinase-mediated ablation of LoxP-flanked Jnk1 alleles. Our results demonstrate that ablation of Jnk1 from airway epithelia resulted in a strong protection from bleomycin- or adenovirus expressing active transforming growth factor beta-1
The data reported herein show the capacity of NSC 651016 to act as an inhibitor of CXCL12-mediated angiogenesis in a variety of in vitro and in vivo angiogenesis assays. Furthermore, these data suggest the potential application of NSC 651016 as an antiangiogenic therapy because it blocked endothelial cell migration, capillary-like tube formation, and angiogenesis. Furthermore, NSC 651016 may have wider applications in cancer therapy. CXCL12 has been implicated in the proliferation of astrocytes (14) by activating extracellular signal-regulated kinase 1/2 but not p38 or stress-activated protein kinase/c-Jun NH2-terminal kinase pathways (14) , therefore, CXCL12 may have a direct role in pathological glial cell proliferation such as reactive gliosis and brain tumor formation. Thus, blockade of CXCL12 function by NSC 651016 may have direct therapeutic benefits for certain brain cancers, one of the most refractory tumor types known. Additionally, CXCL12 participates in cancer cell metastasis by ...
Changes in cell shape affect many critical cellular and bodily processes, like wound healing and developmental events, and when gone awry, metastatic processes in cancer. Evolutionarily conserved signaling pathways govern regulation of these cellular changes. The Jun-N-terminal kinase pathway regulates cell stretching during wound healing and normal development. An extensively studied developmental process is embryonic dorsal closure in fruit flies, a well-established model for the regulation and manner of this cell shape changes.. Here researchers from the National Autonomous University of Mexico describe and characterize a processed, long non-coding RNA locus, acal, that adds a new layer of complexity to the Jun-N-terminal kinase signaling, acting as a negative regulator of the pathway. acal modulates the expression of two key genes in the pathway: the scaffold protein Cka, and the transcription factor Aop. Together, they enable the proper level of Jun-N-terminal kinase pathway activation to ...
We have identified a novel serine/threonine kinase, NIK, that interacts with the SH3 domains of Nck. Overexpression of NIK constitutively activated the JNK/SAPK pathway. NIK interacts with MEKK1 in cells and likely signals through MEKK1 to activate JNK, suggesting that NIK directly regulates MEKK1 activity. We found that NIK contains a regulatory domain in its C‐terminus that is conserved in two other members of this kinase family. This domain mediates the association of NIK with MEKK1 and is critical for NIK activation of the SAPK pathway, suggesting that the C‐terminal domain of these proteins encodes a new protein domain family that couples these kinases to the SAPK pathway, possibly by interacting with MEKK1. Our finding that NIK also interacts with Nck suggests that SH2/SH3 adaptor proteins couple NIK and related kinases to activation of the SAPK/JNK pathway by different receptors.. Studies in Saccharomyces cerevisiae have shown that a serine/threonine kinase, Ste20, acts upstream of ...
3VUM: Seven cysteine-deficient mutants depict the interplay between thermal and chemical stabilities of individual cysteine residues in mitogen-activated protein kinase c-Jun N-terminal kinase 1
3VUM: Seven cysteine-deficient mutants depict the interplay between thermal and chemical stabilities of individual cysteine residues in mitogen-activated protein kinase c-Jun N-terminal kinase 1
The c-Jun NH2-terminal kinases (JNK) are evolutionarily conserved serine/threonine protein kinases that are activated by proinflammatory cytokines, environmental stress, and genotoxic agents. These kinases play key regulatory roles within a cell by coordinating signals from the cell surface to nuclear transcription factors. JNK phosphorylates the amino terminal domain of all three Jun transcription factors (JunB, c-Jun and JunD) all members of the AP-1 family. The activated transcription factors modulate gene expression to generate appropriate biological responses, including cell migration, proliferation, differentiation and cell death. The role of the JNK signaling pathway in cell death/apoptosis is controversial, both pro-apoptotic and pro-survival roles have been attributed to JNK. The mechanism that enables the JNK signaling pathway to mediate both apoptosis and survival is unclear. The aim of this study is to examine the role of TNF-stimulated JNK activation on cell survival. The proinflammatory
The JNK signaling pathway is activated when cells such as neurons are exposed to environmental stress. The JIP proteins are likely to act in this pathway because they bind to JNK, as well as to upstream activators of JNK. A report from Whitmarsh et al. now strengthens the argument that JIPs are scaffolding proteins that coordinate the formation of a JNK-activating module. JIP1 localized to the cell body and to the growth-cone tips of extended neurites in unstimulated murine hippocampal neurons, but upon exposure to various stress stimuli, JIP1 relocalized to the perinuclear region where activated JNK was also found. Neurons from a JIP1-null mouse did not demonstrate stress-induced JNK activation or apoptosis, demonstrating that JIP is required for JNK activation in vivo. Because JIP1 was isolated in a complex with kinesin from mouse brain tissue, the authors speculate that JIP translocation may involve cellular motor proteins. Such a transport mechanism may facilitate signal transduction from ...
In this study, we demonstrated a protective function of ERK in apoptotic events trigged by the physiological stress factor methylglyoxal. Activation of the ERK pathway after PMA treatment resulted in the inhibition of mitochondrial death machinery induced by exposure to MG. Because MG caused JNK activation and activated JNK was sufficient for inducing cytochrome c release from mitochondria, we speculated that ERK is involved in the regulation of JNK-mediated mitochondrial dysfunction. In support of this hypothesis, the ERK and the JNK signals, which are triggered by PMA and MG, respectively, were integrated on mitochondria. We further demonstrated that active ERK represses JNK-induced leakage of cytochrome c in vitro. Because the protective effect of ERK on JNK-induced mitochondrial death machinery has not been demonstrated directly in previous studies, our study is the first in which direct evidence of their opposing effects on mitochondrial injury was obtained using a cell-free system.. Our ...
BLASTX 2.0a10MP-WashU [15-May-1997] [Build 16:56:44 May 19 1997] Reference: Gish, Warren (1994-1997). unpublished. Gish, Warren and David J. States (1993). Identification of protein coding regions by database similarity search. Nat. Genet. 3:266-72. Notice: statistical significance is estimated under the assumption that the equivalent of one entire reading frame in the query sequence codes for protein and that significant alignments will involve only coding reading frames. Query= 914074 (611 letters) Translating both strands of query sequence in all 6 reading frames Database: ../../_tempdbs/nrdb 267,798 sequences; 79,948,537 total letters. Searching....10....20....30....40....50....60....70....80....90....100% done Smallest Sum Reading High Probability Sequences producing High-scoring Segment Pairs: Frame Score P(N) N A gi,1916549 (U50966) DJNK [Drosophila melanog... +2 184 2.0e-13 1 A gi,1656058 (U73196) Jun-N-terminal kinase [D... +2 184 3.2e-13 1 A gi,1857041 (U49180) JNK protein kinase ...
Background/Aims: aberrant c-Jun N-terminal kinase (JNK) activation has been linked to hepatocellular carcinoma (HCC) in mouse models. It remains unclear whether JNK activation plays an important role in human HCC and, if so, how JNK signaling contributes to the initiation or progression of HCC. Methods: the JNK activation, global gene expression, and the status of histone H3 methylations were mea
The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis in the course interaction with Bim after transitory centred cerebral ischemia. High internal tension of the bladder has a occasion likelihood to d‚nouement develop in bladderВ-ureter reflux and harm the kidney in a retrograde frame, which is the dean origin of cessation for the benefit of the new produce of SCI [9, 10]. Unfortunately, Pneumovax 23 does not protect against nonbacteremic disease (ie, pneumonia without bloodstream infection) (French et al 2000; Whitney et al 2003) buy 5 mg zyrtec with visa allergy medicine 4h2. When a neonate who has previously been diagnosed with an innate mistaken of metabolism is hospitalized, the sister must decide the prescribed fast and medications so these may be continued while in the sickbay setting. On place against, another over inaugurate a significant reduction in the troop of rapid ripples recorded with pier clinical electrodes ...
Cytokines and stress-inducing stimuli signal through c-Jun N-terminal kinase (JNK) using a diverse and only partially defined set of downstream effectors. In ...
The involvement of JNK and NRF2 pathway in apoptosis induced by AATBC knockdownA. 36 hours after transfection, levels of JNK, p-JNK, p-p38, p-ERK1/2 and NRF2 we
Pendedahan sel Jurkat kepada ekstrak biji anggur - GSE mengakibatkan peningkatan dose- dan masa yang bergantung kepada di apoptosis dan pengaktifan caspase,
Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK
TY - JOUR. T1 - Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kB activation through TBK1. AU - Abe, Takayuki. AU - Barber, Glen N.. PY - 2014. Y1 - 2014. N2 - STING (stimulator of interferon genes) is known to control the induction of innate immune genes in response to the recognition of cytosolic DNA species, including the genomes of viruses such as herpes simplex virus 1 (HSV-1). However, while STING is essential for protection of the host against numerous DNA pathogens, sustained STING activity can lead to lethal inflammatory disease. It is known that STING utilizes interferon regulatory factor 3 (IRF3) and nuclear factor kB (NF-kB) pathways to exert its effects, although the signal transduction mechanisms remain to be clarified fully. Here we demonstrate that in addition to the activation of these pathways, potent induction of the Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) pathway was similarly observed in ...
TY - JOUR. T1 - Stimulation of Jun N-terminal kinase (JNK) by gonadotropin-releasing hormone in pituitary αt3-1 cell line is mediated by protein kinase C, c-Src, and CDC42. AU - Levi, N. L.. AU - Hanoch, T.. AU - Benard, Outhiriaradjou. AU - Rozenblat, M.. AU - Harris, D.. AU - Reiss, N.. AU - Naor, Z.. AU - Seger, R.. PY - 1998. Y1 - 1998. N2 - The signaling of ligands operating via heterotrimeric G proteins is mediated by a complex network that involves sequential phosphorylation events. Signaling by the G protein-coupled receptor GnRH was shown to include elevation of Ca2+ and activation of phospholipases, protein kinase C (PKC) and extracellular signal-regulated kinase (ERK). In this study, GnRH was shown to activate Jun N-Terminal Kinase (JNK)/SAPK in αT3-1 cells in a PKC- and tyrosine kinase-dependent manner. GnRH as well as tumor-promoting agent (TPA) also increased c-Src activity, which peaked at 2 min after GnRH stimulation and was sensitive both to PKC and to tyrosine kinase ...
TT-232 is a somatostatin analogue containing a five-residue ring structure. The present report describes TT-232-induced signalling events in A431 cells, where a 4-h preincubation with the peptide irreversibly induced a cell death program, which involves DNA-laddering and the appearance of shrunken nuclei, but is unrelated to somatostatin signalling. Early intracellular signals of TT-232 include a transient two-fold activation of the extracellular signal-regulated kinase (ERK2) and a strong and sustained activation of the stress-activated protein kinases c-Jun NH(2)-terminal kinase (JNK)/SAPK and p38MAPK. Blocking the signalling to ERK or p38MAPK activation had no effect on the TT-232-induced cell killing. At the commitment time for inducing cell death, TT-232 decreased EGFR-tyrosine phosphorylation and prevented epidermial growth factor (EGF)-induced events like cRaf-1 and ERK2 activation. Signalling to ERK activation by FCS, phorbol 12-myristate 13-acetate (PMA) and platelet-derived growth ...
Stress-activated protein kinases (SAPKs) are stimulated by cell damaging agents as well as by physiological receptor agonists. In this study we show that human platelets contain the isoforms SAPK2a, SAPK2b, SAPK3 and SAPK4 as determined by immunoblotting with specific antibodies. All four kinases were activated in thrombin-stimulated platelets whereas only SAPK2a and SAPK2b were significantly stimulated by collagen. All four isoforms were able to phosphorylate wild-type human cPLA2in vitro, although to different extents, but not cPLA2 mutants that had Ser505 replaced by alanine. Phosphorylation at Ser505 was confirmed by phosphopeptide mapping using microbore HPLC. SAPK2a and 42-kDa mitogen-activated protein kinase incorporated similar levels of phosphate into cPLA2 relative to the ability of each kinase to stimulate phosphorylation of myelin basic protein. SAPK2b and SAPK4 incorporated less phosphate, and cPLA2 was a poor substrate for SAPK3. The inhibitor of SAPK2a and SAPK2b, SB 202190, ...
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The regulation of innate immune responses to pathogens occurs through the interaction of Toll-like receptors (TLRs) with pathogen-associated molecular patterns and the activation of several signaling pathways whose contribution to the overall innate immune response to pathogens is poorly understood. We demonstrate a mechanism of control of murine macrophage responses mediated by TLR1/2 heterodimers through c-Jun N-terminal kinase 1 (JNK1) activity. JNK controls tumor necrosis factor alpha production and TLR-mediated macrophage responses to Borrelia burgdorferi, the causative agent of Lyme disease, and the TLR1/TLR2-specific agonist PAM(3)CSK(4). JNK1, but not JNK2, activity regulates the expression of the tlr1 gene in the macrophage cell line RAW264.7, as well as in primary CD11b(+) cells. We also show that the proximal promoter region of the human tlr1 gene contains an AP-1 binding site that is subjected to regulation by the kinase and binds two complexes that involve the JNK substrates c-Jun, ...
The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain.We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation.Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of
Background Roux‐en‐Y gastric bypass (RYGB) reduces obesity‐associated comorbidities and cardiovascular mortality. RYGB improves endothelial dysfunction, reducing c‐Jun N‐terminal kinase (JNK) vascular phosphorylation. JNK activation links obesity with insulin resistance and endothelial dysfunction. Herein, we examined whether JNK1 or JNK2 mediates obesity‐induced endothelial dysfunction and if pharmacological JNK inhibition can mimic RYGB vascular benefits. Methods and Results After 7 weeks of a high‐fat high‐cholesterol diet, obese rats underwent RYGB or sham surgery; sham-operated ad libitum-fed rats received, for 8 days, either the control peptide D‐TAT or the JNK peptide inhibitor D‐JNKi‐1 (20 mg/kg per day subcutaneous). JNK peptide inhibitor D‐JNKi‐1 treatment improved endothelial vasorelaxation in response to insulin and glucagon‐like peptide‐1, as observed after RYGB. Obesity increased aortic phosphorylation of JNK2, but not of JNK1. RYGB and JNK peptide ...
The JUN amino terminal kinases (JNK) are activated by cellular stress and play a part in apoptosis. Genetic susceptibility to psychiatric disorders in humans is associated with disruption of JNK pathway signalling, and this stress kinase appears to regulate anxiety and depression-like behaviours in mice. JNK1 plays an active role in the developing brain. It is also expressed in adulthood, but we know less about its role. Even so, might JNK inhibitors have therapeutic potential?. This is the question being asked by Eleanor Coffey, University of Turku, Finland.. JNK1 knockout animals display less anxiety than wild type animals. Dr Coffey and colleagues were not able to show that acute inhibition of JNK1 altered anxiety behaviour. But chronic treatment with an inhibitor decreased "anxious" behaviour in adult mice and increased neurogenesis in the hippocampus. In patients, hippocampal neurogenesis is required for the action of antidepressants; so this phenomenon may be relevant to treatment. In Dr ...
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387518839 - EP 1027429 A4 2002-11-20 - JNK3 MODULATORS AND METHODS OF USE - [origin: WO9918193A1] The c-Jun NH2-terminal kinase (JNK) group of MAP kinases are activated by exposure of cells to environmental stress. The role of JNK in the brain was examined by targeted disruption of the gene that encodes the neuronal isoform JNK3. It was found that JNK3 is required for the normal response to seizure activity. Methods of screening for molecules and compounds that decrease JNK3 expression or activity are described. Such molecules or compounds are useful for treating disorders involving excitotoxicity such as seizure disorders, Alzheimer s disease, Huntington disease, Parkinson s disease, and ischaemia.[origin: WO9918193A1] The c-Jun NH2-terminal kinase (JNK) group of MAP kinases are activated by exposure of cells to environmental stress. The role of JNK in the brain was examined by targeted disruption of the gene that encodes the neuronal isoform JNK3. It was found that JNK3 is required for the normal
Homodimer. Forms higher oligomers under stress conditions. Interacts with BCL2L11. Interaction with BCL2L11 promotes BAX oligomerization and association with mitochondrial membranes, with subsequent release of cytochrome c. Forms heterodimers with BCL2, BCL2L1 isoform Bcl-X(L), BCL2L2, MCL1 and A1. Interacts with SH3GLB1 and HN. Interacts with SFN and YWHAZ; the interaction occurs in the cytoplasm. Under stress conditions, JNK-mediated phosphorylation of SFN and YWHAZ, releases BAX to mitochondria. Isoform Sigma interacts with BCL2A1 and BCL2L1 isoform Bcl-X(L). Interacts with RNF144B, which regulates the ubiquitin-dependent stability of BAX. Interacts with CLU under stress conditions that cause a conformation change leading to BAX oligomerization and association with mitochondria. Does not interact with CLU in unstressed cells. Interacts with FAIM2/LFG2. Interacts with RTL10/BOP. Interacts (via a C-terminal 33 residues) with NOL3 (via CARD domain); inhibits BAX activation and translocation and ...
Because silymarin exhibits anticarcinogenic, anti-inflammatory, and cytoprotective effects, we hypothesized that these effects of silymarin are mediated through suppression of NF-κB activation, an early mediator of the pleiotropic effects of TNF. Our results clearly demonstrate that silymarin is a potent inhibitor of NF-κB activation induced by a wide variety of inflammatory agents. The inhibition of NF-κB activation by silymarin correlated with suppression of IκBα phosphorylation and degradation, p65 nuclear translocation, and NF-κB-dependent reporter gene transcription. Silymarin also inhibited the activation of MEK and JNK and the apoptosis induced by TNF.. There are several possibilities for how silymarin might inhibit TNF-induced NF-κB activation. We showed that silymarin does not interfere with the binding of NF-κB to the consensus DNA binding site. NF-κB activation requires sequential phosphorylation, ubiquitination, and degradation of IκBα. Because silymarin blocks IκBα ...
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TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA …
You are viewing an interactive 3D depiction of the molecule anthra[2,1,9-def:6,5,10-def]diisoquinoline-1,3,8,10(2h,9h)-tetrone, 2,9-dimethyl- (C26H34N2O4) from the PQR.
Kubasiak, L.A., Frazier, D., Dougherty, C. J., Li, H., Bishopric, N.H., and Webster, K.A. (2004) Mitochondrial Signals Initiate the Activation of c-Jun N-terminal Kinase (JNK) by Hypoxia-Reoxygenation. FASEB Journal. 18(10), 1060-1070. ...
Click on a genes description to view its network relationships with genes known to be involved in "positive regulation of jnk cascade" ...
The sinusoidal hepatic stellate cells (HSC) are the major effectors during hepatic fibrogenesis and cirrhosis. During the early stages of hepatic injury associated with cirrhosis, the normally quiescent, vitamin A-storing HSC transform into actively proliferating, collagen-producing myofibroblast-like cells (34). Alcohol is one of the principal causes of cirrhosis. While the major clinical problem of alcohol-induced hepatic fibrogenesis has been the subject of numerous studies, the precise molecular mechanism(s) which leads to the increase in αI(I) collagen in HSC remains incompletely understood (2, 6, 24, 26, 35,36). It was demonstrated that acetaldehyde, but not ethanol, induced the increase in the αI(I) collagen gene expression (up to 2.5-fold) measured by Northern blots in cultured 3T3 fibroblasts (2). Further studies indicated that acetaldehyde increased the αI(I) collagen gene transcription in cultured HSC demonstrated by transcription run-on assays (4). These previous observations ...
Heart failing occurs because of persistent stress towards the myocardium frequently. (1-AR) and G12, activate the tiny G proteins RhoA, which in turn engages both Jun N-terminal proteins kinase (JNK) and p38 mitogen-activated proteins kinase (MAPK) kinase cascades (4C6). These research stage toward tension signaling as a significant contributor towards the hypertrophic response. In this issue, del Vescovo et al. describe an intriguing new connection between adrenergic, small GTPase, and cytokine signaling that regulates stress effects on cardiac remodeling (7). del Vescovo and colleagues have identified a robust protein-protein conversation between A-kinase-anchoring protein (AKAP)CLbc and IB kinase (IKK), a crucial regulator of NF-B signaling. Interestingly, AKAP-Lbc is an AKAP that also possesses Rho guanine PP242 nucleotide exchange factor (GEF) activity and acts as a scaffold for multiple kinases involved in cardiomyocyte function (5, 8, 9). In this context, AKAP-Lbc promotes fetal gene ...
Component of a protein kinase signal transduction cascade. Mediator of TGF-beta signal transduction. Responsible for activation of the JNK MAPK pathway (basket, bsk and hemipterous, hep) in response to LPS. Component of the NF-kappa-B pathway; relish-mediated JNK inhibition involves proteasomal degradation of Tak1; certain targets of Relish that are induced during immune responses may facilitate destruction of Tak1 and switch off the JNK cascade. Participates in diverse roles such as control of cell shape and regulation of apoptosis.