Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In contrast to the extensive studies on the role of transforming growth factor-beta (TGF-beta) in regulating cell proliferation, differentiation, and apoptosis over the past decade, relatively little is known about the exact role of TGF-beta signaling in regulating host response in infectious diseases. Most of the recent studies have suggested that TGF-beta inhibits macrophage activation during infections with pathogens such as Trypanosoma cruzi and Leishmania, thereby favoring virulence. In certain situations, however, there is also evidence that TGF-beta has been correlated with enhanced resistance to microbes such as Candida albicans, thus benefiting the host. Despite these distinct observations that mainly focused on macrophages, little is known about how TGF-beta regulates host primary innate defensive responses, such as up-regulation of mucin, in the airway epithelial cells. Moreover, how the TGF-beta-Smad signaling pathway negatively regulates p38 mitogen-activated protein kinase (MAPK), a key pathway mediating host response to bacteria, still remains largely unknown. Here we show that nontypeable Haemophilus influenzae, a major human bacterial pathogen of otitis media and chronic obstructive pulmonary diseases, strongly induces up-regulation of MUC5AC mucin via activation of the Toll-like receptor 2-MyD88-dependent p38 path-way. Activation of TGF-beta-Smad signaling, however, leads to down-regulation of p38 by inducing MAPK phophatase-1, thereby acting as a negative regulator for MUC5AC induction. These studies may bring new insights into the novel role of TGF-beta signaling in attenuating host primary innate defensive responses and enhance our understanding of the signaling mechanism underlying the cross-talk between TGF-beta-Smad signaling pathway and the p38 MAPK pathway.
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PMID:Transforming growth factor-beta-Smad signaling pathway negatively regulates nontypeable Haemophilus influenzae-induced MUC5AC mucin transcription via mitogen-activated protein kinase (MAPK) phosphatase-1-dependent inhibition of p38 MAPK. 1273 93

Many of the fibrogenic effects of transforming growth factor-beta (TGF-beta) might be mediated by connective tissue growth factor (CTGF). The present study investigates the role of mitogen-activated protein (MAP) kinase in the expression of CTGF mRNA in the human lung fibroblast line, HFL-1. TGF-beta1 enhanced CTGF mRNA levels in a time- and concentration-dependent manner, and this enhancement was also dependent upon transcription. Inhibition of p38 MAP kinase or extracellular signal-regulated kinase (ERK) activation did not affect TGF-beta1-induced CTGF expression. On the other hand, specific inhibitors of phosphatidylinositol 3-kinase (PI3K) suppressed TGF-beta1-induced CTGF expression in a concentration-dependent manner. TGF-beta1 activated c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors dose-dependently suppressed TGF-beta1-induced JNK, but not p38 MAP kinase activation. Finally, JNK1 and JNK2 antisense oligonucleotides attenuated cellular levels of JNK1 and JNK2 protein, respectively, and repressed TGF-beta1-induced CTGF expression. These results suggest that TGF-beta1-induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute.
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PMID:C-Jun-NH2-terminal kinase mediates expression of connective tissue growth factor induced by transforming growth factor-beta1 in human lung fibroblasts. 1276 Sep 70

Osteoarthritis (OA) is a debilitating, progressive disease of diarthrodial joints associated with aging. At the molecular level, OA is characterized by an imbalance between anabolic (i.e. extracellular matrix biosynthesis) and catabolic (i.e. extracellular matrix degradation) pathways in which articular cartilage is the principal site of tissue injury responses. The pathophysiology of OA also involves the synovium in that 'nonclassical' inflammatory synovial processes contribute to OA progression. Chondrocytes are critical to the OA process in that the progression of OA can be judged by the vitality of chondrocytes and their ability to resist apoptosis. Growth factors exemplified by insulin-like growth factor-1, its binding proteins and transforming growth factor-beta contribute to anabolic pathways including compensatory biosynthesis of extracellular matrix proteins. Catabolic pathways are altered by cytokine genes such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) which are upregulated in OA. In addition, IL-1 and TNF-alpha downregulate extracellular matrix protein biosynthesis while concomitantly upregulating matrix metalloproteinase (MMP) gene expression. When MMPs are activated, cartilage extracellular matrix degradation ensues apparently because levels of endogenous cartilage MMP inhibitors cannot regulate MMP activity. Therapeutic strategies designed to modulate the imbalance between anabolic and catabolic pathways in OA may include neutralizing cytokine activity or MMP gene expression or inhibiting signaling pathways which result in apoptosis dependent on mature caspase activity or mitogen-activated protein kinase (MAPK) activity. MAPK activity appears critical for regulating chondrocyte and synoviocyte apoptosis and MMP genes.
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PMID:Pathophysiological mechanisms in osteoarthritis lead to novel therapeutic strategies. 1278 40

Keloids are benign dermal tumors, characterized by invasive growth of fibroblasts and concomitant increased biosynthesis of extracellular matrix components, with unclear etiology. We previously demonstrated that keloid fibroblasts overexpress insulin-like growth factor-I receptor. In investigating the role of insulin-like growth factor-I receptor overexpression, insulin-like growth factor-I and transforming growth factor-beta interaction was examined in relation to extracellular matrix protein production in cultured human and mouse fibroblasts. Western blotting revealed that collagen type I was expressed in keloid and normal fibroblasts, and its expression was increased by transforming growth factor-beta stimulation more significantly in keloid rather than in normal fibroblasts. Insulin-like growth factor-I and transforming growth factor-beta1 costimulation markedly increased extracellular matrix proteins (collagen type I, fibronectin, and plasminogen activator inhibitor-1) compared with cultures with transforming growth factor-beta1 alone. Insulin-like growth factor-I treatment alone had no stimulatory effect. Real-time reverse transcription-polymerase chain reaction confirmed parallel collagen type I messenger RNA level changes. Luciferase assays were conducted to investigate intracellular signaling pathways in this synergistic stimulation using a mouse fibroblast cell line. Transforming growth factor-beta1 (1 or 10 ng per ml) increased the specific signaling activity approximately 10-fold, whereas the increase with insulin-like growth factor-I (100 ng per ml) was less than 2-fold compared with basal activity; however, the combination of transforming growth factor-beta1 and insulin-like growth factor-I resulted in an approximately 25-fold increase. Insulin-like growth factor-I markedly enhanced transforming growth factor-beta-induced phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor-2. Luciferase assay showed that this synergistic effect was attenuated by the p38 mitogen-activated protein kinase specific inhibitor SB203580 or phosphatidylinositol 3-kinase inhibitor wortmannin, but not by the mitogen-activated protein kinase/extracellular-signal-regulated protein kinase kinase inhibitor PD98059. These results indicate that insulin-like growth factor-I enhances transforming growth factor-beta-induced keloid formation through transforming growth factor-beta postreceptor signal cross-talk, mainly via the p38 mitogen-activated protein kinase/activating transcription factor-2 pathway.
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PMID:Insulin-like growth factor-I enhances transforming growth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts. 1278 20

As shown previously, transforming growth factor-beta (TGF-beta) plays an important role during the period of developmental cell death in the nervous system. As with neurons, oligodendrocytes are generated in excess and eliminated by apoptosis. The present study was aimed at investigating the possible interaction of TGF-beta with tumor necrosis factor-alpha (TNF-alpha) in the regulation of cell death in oligodendroglial precursor cells and analyzing the underlying signaling mechanisms. We show that both factors induce apoptosis independently, but cooperate when applied together. The investigation of the signaling events revealed an important role of the JNK pathway during induction of apoptosis. TGF-beta seemed to be more efficient at inducing a release in cytochrome c from mitochondria than TNF-alpha. This might be the consequence of decreased Bcl-xL levels observed in cells treated with TGF-beta but not with TNF-alpha. Both factors stimulated caspase-3 activity, which could be inhibited by caspase-8 or caspase-9 inhibitors. Therefore, we conclude that TNF-alpha and TGF-beta affect partially common pathways but also regulate different steps in the apoptotic cascade.
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PMID:Transforming growth factor-beta and tumor necrosis factor-alpha cooperate to induce apoptosis in the oligodendroglial cell line OLI-neu. 1286 66

Advanced glycation end products (AGEs) are produced by the non-enzymatic glycation of proteins and lipids. AGE levels are pathologically elevated in a number of inflammatory diseases and in diabetes mellitus. There is evidence that AGEs, acting through the receptor for AGEs, contribute to diabetic complications. Nephropathy is a major complication of diabetes mellitus. However, the initiating molecular events that trigger diabetic renal disease are unknown. Renal mesangial cells produce excess extracellular matrix in response to treatment with transforming growth factor-beta, and excess mesangial cell matrix production, by impairing glomerular filtration, contributes to diabetic nephropathy. AGEs are known to trigger the autocrine production and release of transforming growth factor-beta. However, it is unclear how AGEs signal in mesangial cells. Here we show that treatment of mesangial cells with AGEs and with the receptor for AGEs agonist S100 triggers activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3K) pathways. AGEs trigger the GTP loading of mesangial cell Ras, and AGE activation of ERK requires Ras. We observe that Ki-Ras, but not Ha-Ras, is the target of AGE action. Surprisingly, inhibition of PI3K blocks both ERK and Ki-Ras activation. We also observe that activation of ERK and the PI3K target kinase protein kinase-B is blocked with free radical scavengers, indicating a role for reactive oxygen species in AGE recruitment of PI3K. Thus, AGEs signal to Ki-Ras and ERK through reactive oxygen species-dependent activation of PI3K.
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PMID:Phosphatidylinositol 3'-kinase-dependent activation of renal mesangial cell Ki-Ras and ERK by advanced glycation end products. 1287 51

The multilineage differentiation potential of adult tissue-derived mesenchymal progenitor cells (MPCs), such as those from bone marrow and trabecular bone, makes them a useful model to investigate mechanisms regulating tissue development and regeneration, such as cartilage. Treatment with transforming growth factor-beta (TGF-beta) superfamily members is a key requirement for the in vitro chondrogenic differentiation of MPCs. Intracellular signaling cascades, particularly those involving the mitogen-activated protein (MAP) kinases, p38, ERK-1, and JNK, have been shown to be activated by TGF-betas in promoting cartilage-specific gene expression. MPC chondrogenesis in vitro also requires high cell seeding density, reminiscent of the cellular condensation requirements for embryonic mesenchymal chondrogenesis, suggesting common chondro-regulatory mechanisms. Prompted by recent findings of the crucial role of the cell adhesion protein, N-cadherin, and Wnt signaling in condensation and chondrogenesis, we have examined here their involvement, as well as MAP kinase signaling, in TGF-beta1-induced chondrogenesis of trabecular bone-derived MPCs. Our results showed that TGF-beta1 treatment initiates and maintains chondrogenesis of MPCs through the differential chondro-stimulatory activities of p38, ERK-1, and to a lesser extent, JNK. This regulation of MPC chondrogenic differentiation by the MAP kinases involves the modulation of N-cadherin expression levels, thereby likely controlling condensation-like cell-cell interaction and progression to chondrogenic differentiation, by the sequential up-regulation and progressive down-regulation of N-cadherin. TGF-beta1-mediated MAP kinase activation also controls WNT-7A gene expression and Wnt-mediated signaling through the intracellular beta-catenin-TCF pathway, which likely regulates N-cadherin expression and subsequent N-cadherin-mediated cell-adhesion complexes during the early steps of MPC chondrogenesis.
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PMID:Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. 1289 25

5-Fluorouracil (5-FU), a pyrimidine analog widely used in cancer chemotherapy and in glaucoma surgery, has recently shown some efficacy in the treatment of keloids, scars that overgrow the boundaries of original wounds. Given the physiopathological importance of transforming growth factor-beta (TGF-beta) in keloid and scar formation, we have examined whether the clinical benefits from 5-FU treatment may result from its capacity to interfere with TGF-beta signaling and resulting activation of type I collagen gene expression. Using various molecular approaches to study the mechanisms underlying 5-FU effects, we have demonstrated that 5-FU antagonizes TGF-beta-driven COL1A2 transcription and associated type I collagen production by dermal fibroblasts. In addition, 5-FU inhibits both SMAD3/4-specific transcription and formation of SMAD/DNA complexes induced by TGF-beta. 5-FU induces c-Jun phosphorylation and activates both AP-1-specific transcription and DNA binding. Overexpression of an antisense c-jun expression vector, or that of a dominant-negative form of MKK4 that interferes with c-Jun N-terminal kinase (JNK) activation, blocks the inhibitory activity of 5-FU on TGF-beta-induced COL1A2 transcription. Furthermore, in a cellular context devoid of JNK activity (i.e., JNK-/- fibroblasts), 5-FU inhibits neither formation of SMAD/DNA complexes nor SMAD-driven COL1A2 transcription in response to TGF-beta. Together, these results identify 5-FU as a potent inhibitor of TGF-beta/SMAD signaling, capable of blocking TGF-beta-induced, SMAD-driven up-regulation of COL1A2 gene expression in a JNK-dependent manner. We thus provide a molecular explanation to the observed clinical benefits of 5-FU in the treatment of keloids and hypertrophic scars.
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PMID:5-fluorouracil blocks transforming growth factor-beta-induced alpha 2 type I collagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 activation. 1292 Feb 8

Although RANK-L is essential for osteoclast formation, factors such as transforming growth factor-beta (TGF-beta) are potent modulators of osteoclastogenic stimuli. To systematically investigate the role of TGF-beta in human osteoclastogenesis, monocytes were isolated from peripheral blood by three distinct approaches, resulting in either a lymphocyte-rich, a lymphocyte-poor, or a pure osteoclast precursor (CD14-positive) cell population. In each of these osteoclast precursor populations, the effect of TGF-beta on proliferation, TRAP activity, and bone resorption was investigated with respect to time and length of exposure. When using the highly pure CD14 osteoclast precursor cell population, the effect of TGF-beta was strongly dependent on the stage of osteoclast maturation. When monocytes were exposed to TGF-beta during the initial culture period (days 1-7), TRAP activity and bone resorption were increased by 40%, whereas the cell number was reduced by 25%. A similar decrease in cell number was observed when TGF-beta was present during the entire culture period (days 1-21), but in direct contrast, TRAP activity, cell fusion, cathepsin K, and matrix metalloproteinase (MMP)-9 expression as well as bone resorption were almost completely abrogated. Moreover, we found that latent TGF-beta was strongly activated by incubation with MMP-9 and suggest this to be a highly relevant mechanism for regulating osteoclast activity. To further investigate the molecular mechanism responsible for the divergent effects of continuous versus discontinuous exposure to TGF-beta, we examined RANK expression and p38 MAPK activation. We found the TGF-beta strongly induced p38 MAPK in monocytes, but not in mature osteoclasts, and that continuous exposure of TGF-beta to monocytes down-regulated RANK expression. The current results suggest that TGF-beta promotes human osteoclastogenesis in monocytes through stimulation of the p38 MAPK, whereas continuous exposure to TGF-beta abrogates osteoclastogenesis through down-regulation of RANK expression and therefore attenuation of RANK-RANK-L signaling.
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PMID:Transforming growth factor-beta controls human osteoclastogenesis through the p38 MAPK and regulation of RANK expression. 1293 9

Long-term administration of glucocorticoids (GCs) causes osteoporosis with a rapid and severe bone loss and with a slow and prolonged bone disruption. Although the involvement of GCs in osteoblastic proliferation and differentiation has been studied extensively, their direct action on osteoclasts is still controversial and not conclusive. In this study, we investigated the direct participation of GCs in osteoclastogenesis. Dexamethasone (Dex) at <10(-8) M stimulated, but at >10(-7) M depressed, receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast formation synergistically with transforming growth factor-beta. The stimulatory action of Dex was restricted to the early phase of osteoclast differentiation and enhanced the priming of osteoclast progenitors (bone marrow-derived monocytes/macrophages) toward differentiation into cells of the osteoclast lineage. The osteoclast differentiation depending on RANKL requires the activation of NF-kappaB and AP-1, and the DNA binding of these transcription factors to their respective consensus cis-elements was enhanced by Dex, consistent with the stimulation of osteoclastogenesis. However, Dex did not affect the RANKL-induced signaling pathways such as the activation of IkappaB kinase followed by NF-kappaB nuclear translocation or the activation of JNK. On the other hand, Dex significantly decreased the endogenous production of interferon-beta, and this cytokine depressed the RANKL-elicited DNA binding of NF-kappaB and AP-1, as well as osteoclast formation. Thus, the down-regulation of inhibitory cytokines such as interferon-beta by Dex may allow the osteoclast progenitors to be freed from the suppression of osteoclastogenesis, resulting in an increased number of osteoclasts, as is observed in the early phase of GC-induced osteoporosis.
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PMID:Dexamethasone enhances osteoclast formation synergistically with transforming growth factor-beta by stimulating the priming of osteoclast progenitors for differentiation into osteoclasts. 1294 1


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