Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Keratinocyte-derived TNF-alpha acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-alpha signalling during skin tumour formation, mice deficient in TNFR1 (TNFR1-/- mice) or TNFR2 (TNFR2-/- mice) were subjected to chemical carcinogenesis. Tumour multiplicity was significantly reduced in TNFR1-/- and TNFR2-/- mice compared to wild-type (wt) mice, suggesting that both receptors have protumour activity. However, TNFR1-/- mice were markedly more resistant to tumour development than TNFR2-/- mice indicating that TNFR1 is the major mediator of TNF-alpha-induced tumour formation. TNFR1 and TNFR2 were both expressed in wt epidermis during tumour promotion and by primary keratinocytes in vitro. TPA-induced c-Jun expression was transient in TNFR1-/- and TNFR2-/- compared to wt epidermis and this was reflected by reduced induction of the AP-1-responsive genes granulocyte/macrophage-colony stimulating factor, matrix metalloproteinase-9 and matrix metalloproteinase-3. These genes were differentially regulated in TNFR1-/- compared to TNFR2-/- epidermis, suggesting that the TNF-alpha receptors act independently via different AP-1 complexes to transduce TNF-alpha signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-alpha bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-alpha signalling in malignancy and provide some rationale for the use of TNF-alpha antagonists in the treatment of cancer.
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PMID:Expression of both TNF-alpha receptor subtypes is essential for optimal skin tumour development. 1466 Oct 63

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative human brain disorders. We sought to investigate molecular signaling mechanisms that govern activation of microglia in apoptotic neuronal degeneration. We report here that the active form of matrix metalloproteinase-3 (MMP-3) was released into the serum-deprived media (SDM) of PC12 cells and other media of apoptotic neuronal cells within 2-6 h of treatment of the cells, and SDM and catalytic domain of recombinant MMP-3 (cMMP-3) activated microglia in primary microglia cultures as well as BV2 cells, a mouse microglia cell line. Both SDM and cMMP-3 induced generation of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, and interleukin-1 receptor antagonist but not IL-12 and inducible nitric oxide synthase, which are readily induced by lipopolysaccharide, in microglia, suggesting that there is a characteristic pattern of microglial cytokine induction by apoptotic neurons. Neither glial cell line-derived neurotrophic factor nor anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta1, were induced. SDM and cMMP-3 extensively released TNF-alpha from microglia and activated the nuclear factor-kappaB pathway, and these microglial responses were totally abolished by preincubation with an MMP-3 inhibitor, NNGH [N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid]. MMP-3-mediated microglial activation mostly depended on ERK (extracellular signal-regulated kinase) phosphorylation but not much on either JNK (c-Jun N-terminal protein kinase) or p38 activation. Conditioned medium of SDM- or cMMP-3-activated BV2 cells caused apoptosis of PC12 cells. These results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration. Therefore, the release of MMP-3 from apoptotic neurons may play a major role in degenerative human brain disorders, such as Parkinson's disease.
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PMID:Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. 1581 1

Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 microg/ml VLDL for 6 h led to 2.8- and 3.7-fold increases in intracellular TGs and FFAs, respectively (P < 0.05). The inflammatory proteins tumor necrosis factor-alpha, interleukin-1beta, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein-1alpha (MIP-1alpha) were all upregulated by at least 2-fold (P < 0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1alpha gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.
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PMID:The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages. 1663 77

Many angiogenesis inhibitors are breakdown products of endogenous extracellular matrix proteins. Plasmin and matrix metalloproteinase-3 generate breakdown products of matrix-bound plasminogen activator inhibitor-1 (PAI-1). We produced a truncated form of PAI-1, rPAI-1(23), that possesses significant anti-angiogenic activity and stimulates high levels of apoptosis in quiescent arterial endothelial cells. Quiescent endothelial cells are less susceptible to apoptosis than angiogenic endothelial cells. The present study was designed to determine the mechanism of the rPAI-1(23) effects in bovine aortic endothelial cells. Apoptosis was measured in annexin V and caspase 3 assays. Expression of death and survival signaling molecules were examined by Western blot and kinase activity. Fibroblast growth factor 2 (FGF2) functions were analyzed in angiogenesis assays. The early response to rPAI-1(23) was an increase in annexin V-positive cells and phosphorylated (p) JNK isoform expression followed by an increase in p-Akt and p-c-Jun expression. Caspase 3 was activated at 4 h, whereas p-Akt was reduced to control levels. By 6 h of rPAI-1(23) treatment cell number was reduced by 35%, and p-c-Jun and p-JNK were degraded by proteasomes. Confocal microscopic images showed increased amounts of FGF2 in the extracellular matrix. However, rPAI-1(23) blocked FGF2 signaling through FGF receptor 1 and syndecan-4, inhibiting cell migration, tubulogenesis, and proliferation. Exogenous FGF2 stimulation could not reverse these effects. We conclude that rPAI-1(23) stimulation of apoptosis in BAEC triggers a cascade of death versus survival events that includes release of FGF2. The rPAI-1(23) anti-angiogenic activity inhibits FGF2 pro-angiogenic functions by blocking FGF2 signaling through FGF receptor 1 and syndecan-4 and downstream effectors p-Akt, p-JNK, and p-c-Jun.
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PMID:The anti-angiogenic activity of rPAI-1(23) inhibits fibroblast growth factor-2 functions. 1695 Jul 76

Stratifin is a member of 14-3-3 protein family, a highly conserved group of proteins constituted by seven isoforms. They are involved in numerous crucial intracellular functions such as cell cycle and apoptosis, regulation of signal transduction pathways, cellular trafficking, cell proliferation and differentiation, cell survival, and protein folding and processing, among others. At epidermal level, stratifin (also called 14-3-3 sigma) has been described as molecule with relevant functions. For instance, this isoform is a marker associated with keratinocyte differentiation. In this maturation process, the presence of dominant negative molecules of p53 induces a "stemness condition" of keratinocyte precursor cells and suppression of stratifin expression. In addition, the recently described keratinocyte-releasable form of stratifin is involved in dermal fibroblast MMP-1 over-expression through c-Fos and c-Jun activity. This effect is mediated, at least in part, by p38 mitogen-activated protein kinase (MAPK). Other MMP family members such as stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), neutrophil collagenase (MMP-8), and membrane-type MMP-24 (MT5-MMP) are also up-regulated by stratifin. Within fibroproliferative disorder of skin, hypertrophic scar and keloids exhibit a high content of collagen, proteoglycans, and fibronectin. Thus, the MMP profile induced by stratifin is an interesting starting point to establish new therapeutic tools to control the process of wound healing. In this review, we will focus on site of synthesis and mode of action of stratifin in skin and wound healing.
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PMID:The role of stratifin in fibroblast-keratinocyte interaction. 1764 30

We have previously demonstrated that the active form of matrix metalloproteinase-3 (actMMP-3) is released from dopamine(DA)rgic neurons undergoing apoptosis. Herein, whether actMMP-3 might be generated intracellularly, and if so, whether it is involved in apoptosis of DArgic neurons itself was investigated in primary cultured DArgic neurons of wild-type, MMP-3 knockout animals, and CATH.a cells. During apoptosis, gene expression of MMP-3 is induced, specifically among the various classes of MMPs, generating the proform (55 kDa) which is subsequently cleaved to the catalytically active actMMP-3 (48 kDa) involving a serine protease. Intracellular actMMP-3 activity is directly linked to apoptotic signaling in DArgic cells: (i) Pharmacologic inhibition of enzymatic activity, repression of gene expression by siRNA, and gene deficiency all lead to protection; (ii) pharmacologic inhibition causes attenuation of DNA fragmentation and caspase 3 activation, the indices of apoptosis; and (iii) inhibition of the pro-apoptotic enzyme c-Jun N-terminal protein kinase leads to repression of MMP-3 induction. Under the cell stress condition, MMP-3 is released as actMMP-3 rather than the proform (proMMP-3), and catalytically active MMP-3 added to the medium does not cause cell death. Thus, actMMP-3 seems to have a novel intracellular role in apoptotic DArgic cells and this finding provides an insight into the pathogenesis of Parkinson's disease.
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PMID:A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. 1839 66

The autocrine motility factor (AMF) is a multifunctional protein that is involved in tumor progression including enhanced invasiveness via induction of matrix metalloproteinase-3 (MMP3). The increase in MMP3 was found in an AMF-high production tumor cell line, and c-Jun, c-Fos and mitogen-activated protein kinases (MAPKs) were also highly phosphorylated compared with the parent line. AMF stimulation induced the rapid phosphorylation of the cellular MAPK cascade and MMP3 secretion, which was blocked using a specific MAPK inhibitor. Results of this study suggest that AMF stimulation stimulates MMP3 expression via a MAPK signaling pathway.
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PMID:Autocrine motility factor stimulates the invasiveness of malignant cells as well as up-regulation of matrix metalloproteinase-3 expression via a MAPK pathway. 1848

Identification of Ets-1 interaction partners is critical for understanding its properties. Ets-1 DNA-binding is governed by an intramolecular mechanism called autoinhibition. Ets-1 increases its DNA-binding affinity by counteracting autoinhibition through binding either to a particular organization of Ets binding sites (EBS) in palindrome, as in the Stromelysin-1 promoter, or to EBS adjacent to DNA-binding sites of its partners by combinatorial interactions, as in the Collagenase-1 promoter. Identification of new Ets-1 interaction partners should allow the identification of new functions for this transcription factor. To this end, we fused a biotin tag to Ets-1 protein in order to copurify it and its partners by affinity. For the first time, we cloned, produced in Escherichia coli and purified a biotinylated recombinant Ets-1 protein using the T7-Impact system (New England Biolabs), adapted to induce biotinylation. Nearly 100% biotinylation was attained without altering Ets-1 properties. Biotinylated Ets-1 bound to and transactivated the Stromelysin-1 promoter the same way as native Ets-1 did. It also conserved interactions with known Ets-1 partners such as c-Jun, Erk-2 and Runx-1. In addition, streptavidin pull-down and surface plasmon resonance assays demonstrated that biotinylated Ets-1 is a useful tool for qualitative and quantitative studies of Ets-1 interaction with its partners.
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PMID:Efficient system for biotinylated recombinant Ets-1 production in Escherichia coli: a useful tool for studying interactions between Ets-1 and its partners. 1863 39

Autotaxin (ATX) is an approximately 125-kDa transmembrane protein that is considered to be a tumor progression factor based on its lysophospholipase D activity. Here, we report that lysophosphatidic acid produced by ATX promotes the secretion of matrix metalloproteinase-3 (MMP3) from the human fibrosarcoma cell line HT-1080. The c-Jun N-terminal kinases (JNKs) and c-Jun of HT-1080 cells were rapidly phosphorylated after ATX treatment. A specific JNK inhibitor also exhibited this activation of signaling molecules and MMP3 expression. The present results suggest a novel function of ATX in promoting MMP3 production via the mitogen-activated protein kinase cascade, thereby stimulating tumor cell invasiveness.
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PMID:Autotaxin promotes the expression of matrix metalloproteinase-3 via activation of the MAPK cascade in human fibrosarcoma HT-1080 cells. 1921 32

Solar ultraviolet (UV) radiation, particularly its UVB (290-320 nm) component, is the primary cause of many adverse biological effects including photoageing and skin cancer. UVB radiation causes DNA damage, protein oxidation and induces matrix metalloproteinases (MMPs). Photochemoprevention via the use of botanical antioxidants in affording protection to human skin against UVB damage is receiving increasing attention. Pomegranate, from the tree Punica granatum, contains anthocyanins and hydrolysable tannins and possesses strong antioxidant and anti-tumor-promoting properties. In this study, we determined the effect of pomegranate-derived products--POMx juice, POMx extract and pomegranate oil (POMo)--against UVB-mediated damage using reconstituted human skin (EpiDerm(TM) FT-200). EpiDerm was treated with POMx juice (1-2 microl/0.1 ml/well), POMx extract (5-10 microg/0.1 ml/well) and POMo (1-2 microl/0.1 ml/well) for 1 h prior to UVB (60 mJ/cm(2)) irradiation and was harvested 12 h post-UVB to assess protein oxidation, markers of DNA damage and photoageing by Western blot analysis and immunohistochemistry. Pretreatment of Epiderm with pomegranate-derived products resulted in inhibition of UVB-induced (i) cyclobutane pyrimidine dimers (CPD), (ii) 8-dihydro-2'-deoxyguanosine (8-OHdG), (iii) protein oxidation and (iv) proliferating cell nuclear antigen (PCNA) protein expression. We also found that pretreatment of Epiderm with pomegranate-derived products resulted in inhibition of UVB-induced (i) collagenase (MMP-1), (ii) gelatinase (MMP-2, MMP-9), (iii) stromelysin (MMP-3), (iv) marilysin (MMP-7), (v) elastase (MMP-12) and (vi) tropoelastin. Gelatin zymography revealed that pomegranate-derived products inhibited UVB-induced MMP-2 and MMP-9 activities. Pomegranate-derived products also caused a decrease in UVB-induced protein expression of c-Fos and phosphorylation of c-Jun. Collectively, these results suggest that all three pomegranate-derived products may be useful against UVB-induced damage to human skin.
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PMID:Protective effect of pomegranate-derived products on UVB-mediated damage in human reconstituted skin. 1932 Jul 37


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