Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Fra-1 is overexpressed in a variety of human tumors. Whether MMP-9 expression is regulated by Fra-1 has been contradictory. To clarify the capability of Fra-1 in activating transcription of MMP-9 gene, we analyzed the transcriptional activity of the MMP-9 promoter through the measure of luciferase activities in the MCF-7 cells transiently transfected with Fra-1. The positive regulation of Fra-1 on MMP-9 promoter was not detectable. By the analysis of MMP-9 promoter, a potential Stat3 binding site, just juxtaposed AP-1 consensus sequence, was noticed. The reporter assay showed that MMP-9 promoter was activated remarkably by cotransfection with Fra-1 and Stat3C. DNA affinity precipitation assay confirmed the binding of Stat3 and Fra-1 to the elements of MMP-9 promoter and also revealed c-Jun recruited to Stat3-Fra-1 complex. By immunoprecipitation assay, the Stat3/Fra-1, Stat3/c-Jun and Fra-1/c-Jun complexes were identified in vivo. Our study demonstrated that the activation of MMP-9 promoter is dependent upon interactions of Fra-1/c-Jun with Stat3. A juxtaposed Stat3/AP-1 element plays a crucial role in the manner of enhancersome in the activation of MMP-9 gene. The functional cooperation of the Stat3 and AP-1 transcription factors is required for the transcription of MMP-9 gene.
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PMID:Fra-1 and Stat3 synergistically regulate activation of human MMP-9 gene. 1757 95

Persistent elevation in shear stress within conduit or resistance arteries causes structural luminal expansion, which serves to normalize shear stress while maintaining increased flow to the downstream vasculature. Although it is known that this adaptation involves cellular proliferation and remodeling of the extracellular matrix, the specific cellular events underlying these responses are poorly understood. Matrix metalloproteinases (MMPs) contribute to extensive remodeling of the extracellular matrix in conduit vessels and vein grafts exposed to high flow. However, involvement of MMPs in remodeling of small muscular collateral arteries, which are exposed to less severe increases in shear stress, has not been tested. We utilized an established model of outward remodeling in mesenteric collateral arteries to determine whether MMPs were upregulated during the remodeling response and to test whether MMP activity was required for luminal expansion. By 4 days, MMP-2 and membrane type 1 MMP (MT1-MMP), but not MMP-9, protein levels were significantly elevated in collateral arteries, as assessed by gelatin zymography and immunostaining. MMP-2 and MT1-MMP proteins, together with their respective transcriptional activators c-Jun and Egr-1 were localized predominantly to the smooth muscle layer of the collateral arteries. The general MMP inhibitor doxycycline prevented luminal expansion of collateral arteries but did not affect the endothelial cell proliferative or medial growth responses. In conclusion, this study provides evidence that MMP-2 and MT1-MMP are upregulated in collateral arteries exposed to elevated shear stress and that MMP activity is essential for the full remodeling response that leads to outward luminal expansion.
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PMID:Involvement of MMPs in the outward remodeling of collateral mesenteric arteries. 1764 78

We examined the role of osteopontin (OPN) in NIK- and MEKK1-dependent MMP-9 activation, melanoma growth and lung metastasis and its clinical significance in malignant melanoma. Here we report that OPN induces alphavbeta3 integrin-mediated MEKK1-dependent JNK1 phosphorylation. OPN stimulates NIK- or JNK1-dependent c-Jun expression. In contrast, OPN induces MEKK1-dependent JNK1 activation that leads to downregulation of ERK1/2 activation. OPN triggers NIK- and MEKK1-dependent AP-1 activation whereas NIK-dependent AP-1 activation is independent of JNK1 that leads to pro-MMP-9 activation. In vivo studies indicate that the levels of pNIK and MMP-9 are significantly higher in the OPN-induced primary tumor and metastasized lung compared to control. Clinical data revealed that the enhanced level of OPN and pNIK expression in the skin biopsies correlates with Clark's level and Breslow thickness. Altogether, OPN regulates negative cross-talk between NIK/ERK and MEKK1/JNK1 pathways that controls melanoma progression.
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PMID:Osteopontin stimulates melanoma growth and lung metastasis through NIK/MEKK1-dependent MMP-9 activation pathways. 1778 54

NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinones and quinoid compounds to hydroquinones. Although the role of a homologue, NAD(P)H:quinone oxidoreductase 1 (NQO1), is well defined in oxidative stress, neoplasia, and carcinogenesis, little is known about the mechanism of actions of NQO2 in these cellular responses. Whether NQO2 has any role in tumor necrosis factor (TNF) signaling was investigated using keratinocytes derived from wild-type and NQO2 knockout (NQO2-/-) mice. Although exposure of wild-type cells to TNF led to activation of nuclear factor-kappaB (NF-kappaB) and IkappaBalpha kinase, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation, this cytokine had no effect on NQO2-/- cells. Deletion of NQO2 also abolished TNF-induced c-Jun NH2-terminal kinase, Akt, p38, and p44/p42 mitogen-activated protein kinase activation. The induction of various antiapoptotic gene products (MMP-9, cyclin D1, COX-2, IAP1, IAP2, Bcl-2, cFLIP, and XIAP) by TNF was also abolished in NQO2-/- cells. This correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, Annexin V staining, and caspase activation. In agreement with this, we also found that TNF activated NQO2, and NQO2-specific small interfering RNA abrogated the TNF-induced NQO2 activity and NF-kappaB activation. Overall, our results indicate that deletion of NQO2 plays a differential role in TNF signaling pathway: by suppressing cell survival signals and potentiating TNF-induced apoptosis.
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PMID:Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases. 1794 34

Ganoderma lucidum has been reported to be associated with suppressed motility, invasion and metastasis of several types of cancers, but its mechanism of action remains unclear. In our previous study, lucidenic acids A, B, C and N were isolated from a new strain of G.lucidum and all of them were found to have potential anti-invasive activity on phorbol-12-myristate-13-acetate (PMA)-induced HepG(2) cells by suppressing the matrix metalloproteinase (MMP)-9 activity. Here, the lucidenic acid B (LAB) was used to explore its mechanisms underlying MMP-9 expression of HepG(2) cells. The results showed that the LAB suppressed PMA-induced MMP-9 activity in a dose-dependent transcriptional level. The suppression of PMA-induced MMP-9 expression of HepG(2) cells by LAB was through inactivating phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The treatment of mitogen-activated protein kinase kinase (MEK) inhibitors (PD98059 and U0126) and LAB to HepG(2) cells could result in a synergistic reduction on the MMP-9 expression along with an inhibition on cell invasion. Moreover, LAB also strongly inhibited PMA-stimulated nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA-binding activities of HepG(2) cells in dose-dependent manners. A dose-dependent inhibition on protein levels of NF-kappaB, c-Jun and c-Fos in nuclear by LAB treatment was further observed. In conclusion, we demonstrated that the anti-invasive effects of the LAB on the PMA-induced HepG(2) cells might be through inhibiting the phosphorylation of ERK1/2 and reducing AP-1 and NF-kappaB DNA-binding activities, leading to downregulation of MMP-9 expression.
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PMID:Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kappaB and AP-1. 1802 77

Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) are common head and neck cancers with a high propensity for lymph node (LN) and lung metastasis. Here, we report that LHSCCs express high levels of functional CXCR4 receptors, native for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Primary tumor immunohistochemistry from LHSCC patients has revealed significant expression of CXCR4 and CXCL12. Greater expression of CXCR4 but not that of CXCL12 is correlated with LN and distant metastasis. Reverse transcription-polymerase chain reaction and western blots have demonstrated that CXCR4 messenger RNA (mRNA) and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced extracellular signal-regulated kinase (ERK) pathway activation and the motility/invasiveness of LHSCC cell lines, which were blocked by treatment with a CXCR4 antagonist (AMD3100) and a specific MEK inhibitor (U0126). Results show that the mRNA and protein levels of matrix metalloproteinase (MMP)-13, but not MMP-2 or MMP-9, were elevated in HEp-2 cells in response to CXCL12. Again, U0126 almost inhibited the induction of MMP-13 in HEp-2 cells by stimulating CXCL12. The transcriptional factor, c-Jun, a downstream factor of ERK pathway, was found to be readily phosphorylated and translocated to the nucleus after 10 min of exposure to CXCL12. Blockage of c-Jun activity by transfection with c-jun antisense oligodeoxynucleotide significantly decreased CXCL12-induced MMP-13 expression and cell invasion. CXCL12 seems to enhance LHSCC cell invasion through paracrine-activated CXCR4, which triggers ERK/c-Jun-dependent MMP-13 upregulation.
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PMID:CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway. 1848 24

Quercetin (QUE; 3,5,7,3',4'-tetrahydroxyflavone) has been shown to possess several beneficial biological activities including antitumor, anti-inflammation and antioxidant properties; however, the effects of QUE in preventing invasion by breast carcinoma cells are still undefined. Increases in the protein, messenger RNA and enzyme activity levels of matrix metalloproteinase (MMP)-9 were observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells, and these were blocked by QUE, but not by quercitrin or rutin. A translocation of protein kinase C (PKC)delta from the cytosol to the membrane followed by activation of extracellular signal-regulated kinase (ERK) and c-Jun/activator protein-1 (AP-1) by TPA was demonstrated, and TPA-induced MMP-9 activation and migration were inhibited by the pan PKC inhibitor, GF109203X, the specific PKCdelta inhibitor, rottlerin, an ERK inhibitor (PD98059) and an AP-1 inhibitor (curcumin). Application of QUE significantly suppressed TPA-induced activation of the PKCdelta/ERK/AP-1-signaling cascade. To elucidate the importance of hydroxyl (OH) substitutions to QUE's inhibition of tumor migration, several structurally related flavones of QUE including 3',4'-diOH, 3',4'-diOCH(3), 3,5,7-triOH, 3,4',4'-triOH, 3,3',4'-triOCH(3), luteolin and fisetin were used. Results suggested that OH groups at both C3' and C4' play central roles in QUE's inhibition of TPA-induced MMP-9 activation and migration, and an additional OH at C3, C5 or C7 may increase the inhibitory potency of the 3',4'-diOH flavone against TPA-induced MMP-9 activity and migration. The antitumor invasion and migration effects of breast carcinoma cells induced by QUE with the structure-activity relationship analysis were identified.
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PMID:Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. 1862 48

Upregulation of matrix metalloproteinases (MMPs), especially MMP-9, by oxidized low-density lipoprotein (oxLDL) is implicated in many inflammatory diseases including brain injury. However, the signaling mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes largely remain unknown. Here we report that oxLDL induces expression of proMMP-9 via a MAPK-dependent AP-1 activation in rat brain astrocyte (RBA)-1 cells. Results revealed by gelatin zymography, RT-PCR, and Western blotting analyses showed that oxLDL-induced proMMP-9 gene expression was mediated through Akt, JNK1/2, and p42/p44 MAPK phosphorylation in RBA-1 cells. These responses were attenuated by inhibitors of PI3K (LY294002), JNK (SP600125), and p42/p44 MAPK (PD98059), or transfection with dominant negative mutants and short hairpin RNA. Moreover, we demonstrated that AP-1 (i.e., c-Fos/c-Jun) is crucial for oxLDL-induced proMMP-9 expression which was attenuated by pretreatment with AP-1 inhibitor (curcumin). The regulation of MMP-9 gene transcription by AP-1 was confirmed by oxLDL-stimulated MMP-9 luciferase activity which was totally lost in cells transfected with the AP-1 binding site-mutated MMP-9 promoter construct (mt-AP1-MMP-9). These results suggested that oxLDL-induced proMMP-9 expression is mediated through PI3K/Akt, JNK1/2, and p42/p44 MAPK leading to AP-1 activation. Understanding the regulatory mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes might provide a new therapeutic strategy of brain injuries and diseases.
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PMID:Oxidized low-density lipoprotein induces matrix metalloproteinase-9 expression via a p42/p44 and JNK-dependent AP-1 pathway in brain astrocytes. 1866 53

Tissue transglutaminase (TGase 2) has been reported to have multiple functions in addition to its function as a biological adhesive. To identify its roles, we investigated the effects of TGase 2 on gelatinase activity. The MMP-9 activity of certain cell lines was significantly inhibited with retinoic acid treatment, and this effect was reversed in the presence of a TGase 2 inhibitor. Furthermore, TGase 2 overexpression reduced the MMP-9 protein expression levels and inhibited its activity in both culture media and cell lysate. The decreased mRNA levels of MMP-9 and the results of a promoter assay revealed that TGase 2 may be involved in MMP-9 transcription. Further, data obtained in an immunoprecipitation assay and an electrophoretic mobility shift assay demonstrated that TGase 2 binds to c-Jun and suppresses its binding activity toward AP-1. These results suggest that TGase 2 inhibits MMP-9 via downregulation of MMP-9 transcription activity by blocking the binding of the Jun-fos complex to an AP-1 site.
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PMID:Tissue transglutaminase-induced down-regulation of matrix metalloproteinase-9. 1880 80

Isoliquiritigenin (ISL, 4,2',4'-trihydroxychalcone), which is found in licorice, shallot and bean sprouts, is a potent antioxidant with anti-inflammatory and anti-carcinogenic effects. The purpose of this study was to investigate the effects of ISL treatment on the migration, invasion and adhesion characteristics of DU145 human prostate cancer cells. DU145 cells were cultured in the presence of 0-20 micromol/L ISL with or without 10 microg/L epidermal growth factor (EGF). ISL inhibited basal and EGF-induced cell migration, invasion and adhesion dose dependently. ISL decreased EGF-induced secretion of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and vascular endothelial growth factor (VEGF), but increased TIMP-2 secretion in a concentration-dependent manner. In addition, ISL decreased the protein levels of integrin-alpha2, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), and mRNA levels of uPA, MMP-9, VEGF, ICAM and integrin-alpha2. Furthermore, basal and EGF-induced activator protein (AP)-1 binding activity and phosphorylation of Jun N-terminal kinase (JNK), c-Jun and Akt were decreased after ISL treatment. However, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase was not altered. The JNK inhibitor SP600125 inhibited basal and EGF-induced secretion of uPA, VEGF, MMP-9 and TIMP-1, as well as AP-1 DNA binding activity and cell migration. These results provide evidence for the role of ISL as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of prostate cancer cells. The inhibition of JNK/AP-1 signaling may be one of the mechanisms by which ISL inhibits cancer cell invasion and migration.
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PMID:Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling. 1882 45


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