UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) are thought to play crucial roles in tumor invasion and metastasis. Because we have shown that EBV latent membrane protein 1 (LMP1) enhances MMP-9 expression by activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 (T. Yoshizaki, et al., Proc. Natl. Acad. Sci. USA, 95: 3621-3626, 1998), we therefore tested whether up-regulation of MMP-9 by LMP1 could be correlated with enhanced invasiveness of tumor cells in vitro. Whether aspirin and sodium salicylate could reduce invasiveness and whether LMP1 could enhance MMP-9 expression in tumors grown in nude mice were also tested. C33A cells stably expressing LMP1 had increased expression of MMP-9 and showed greater invasion through reconstituted basement membrane compared with vector-transfected C33A cells (P < 0.02). Treatment with aspirin or sodium salicylate inhibited invasiveness of the LMP1-expressing C33A cells (P < 0.03) and suppressed both the LMP1-induced MMP-9 expression in zymographic analyses and LMP1-induced MMP-9 promoter activity in CAT reporter assays (P < 0.01). Endogenous MMP-2 levels were unaffected by either drug. Both drugs repressed the CAT activity of the truncated MMP-9 promoter construct, which only contained a binding site for AP-1, to the basal level (P < 0.05). Moreover, EMSA indicated that the effects of the salicylates were through the inhibition of not only NF-kappaB but also AP-1 binding activity. Inhibitory effect of salicylates could be reversed by p50/p65 subunits of NF-kappaB or c-Jun overexpression. The inhibitory effect of aspirin on NF-kappaB activity was attributable to the inhibition of IkappaB kinase activity. Finally, tumors derived from C33A cells stably expressing LMP1 grown in nude mice showed enhanced MMP-9 levels compared with tumors derived from vector-transfected C33A cells. This enhancement was inhibited by treatment of the mice with aspirin. These results suggest that aspirin may be able to suppress invasion and metastasis of EBV-associated tumors that express LMP1 by suppression of MMP-9.
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PMID:Aspirin inhibits tumor cell invasiveness induced by Epstein-Barr virus latent membrane protein 1 through suppression of matrix metalloproteinase-9 expression. 1081 Nov 39

Our study examined the expression of AP-1 family members in keratinocytes derived from the rat-4NQO model of oral carcinogenesis in which extremes of epithelial differentiation and tumour cell aggressiveness are evident. The constitutive expression of JunB was diminished in the undifferentiated, more aggressive tumour phenotype compared with the well-differentiated, less aggressive keratinocytes, whereas the expression of other AP-1 family members (c-jun, junD, c-fos, fra1, fra2 and fosB) was either very weak or variable. After transfection of the undifferentiated keratinocytes with junB cDNA, clonal populations were isolated that expressed similar levels of JunB protein as the well-differentiated cells. Both untransfected and transfected cell lines were keratin negative and vimentin positive. Increased expression of JunB in the transfected cells resulted in up-regulation of c-Jun and Fra1 and an enhanced AP-1 activity as demonstrated by transcriptional activation of the prototypic AP-1 dependent promoter, MMP-1. JunB transfected cells grew more quickly than vector-only controls and were refractory to the growth inhibitory effects of TGF-beta1. Over-expression of JunB resulted in the elevated expression of the AP-1 dependent proteinase, MMP-9, whereas the expression of the AP-1 independent enzyme, MMP-2, was unaffected. JunB transfected keratinocytes were highly invasive in an in vitro assay of tumour cell invasion compared with vector controls. The results indicate that increased expression of JunB above baseline levels in undifferentiated rat keratinocytes does not alter epithelial differentiation but enhances the malignant phenotype in vitro, possibly by altering the dynamics of the AP-1 complex.
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PMID:Overexpression of JunB in undifferentiated malignant rat oral keratinocytes enhances the malignant phenotype in vitro without altering cellular differentiation. 1126 71

Calcium antagonists (CAs) are widely prescribed for patients with cardiovascular diseases. CAs have been reported to inhibit smooth muscle cell (SMC) proliferation in addition to their effects on vascular tone. To determine whether CAs potentially affect vascular remodeling, we measured the expression of matrix-degrading enzymes in growth factor-stimulated SMC. Human cultured SMC were stimulated with 10 ng/ml of platelet-derived growth factor (PDGF)-BB with or without a calcium antagonist, diltiazem. In the cell counting assay, diltiazem (10-5 M) alone had no effect on the proliferation of quiescent SMC, however 10-6-10-5 M of diltiazem dose-dependently inhibited PDGF-stimulated SMC proliferation. The inhibitory effects of diltiazem on SMC proliferation were further confirmed by a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and flow cytometry. In Western blotting, matrix metalloproteinase (MMP)-1 (tissue collagenase) but not MMP-2 (72-kDa gelatinase) expression was upregulated by PDGF and phorbol ester (TPA), which were reduced by diltiazem in a dose-dependent manner. The downregulation of MMP-1 expression was consistent with the reduction of collagenolytic activity measured by a FITC-conjugated type I collagen breakdown assay. PDGF-stimulated c-Jun/AP-1 expression, a major transcriptional factor for MMP-1, was not affected by diltiazem. In contrast, intracellular calcium ions measured with a fluorometric assay of Fluo-3AM-loaded cells revealed that the PDGF-stimulated increase in the intracellular calcium content was dose-dependently reduced by diltiazem. Our data suggest that diltiazem inhibits not only proliferation but also MMP-1 expression and collagenolytic activity in PDGF-stimulated SMC. The administration of CAs potentially influences the process of vascular remodeling, and this possibility should be further verified in vivo.
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PMID:Diltiazem, a calcium antagonist, inhibits matrix metalloproteinase-1 (tissue collagenase) production and collagenolytic activity in human vascular smooth muscle cells. 1160 28

Penta-O-galloyl-beta-D-glucose (5GG) inhibited the invasion of highly metastatic mouse melanoma B16F10 cells in vitro, as demonstrated by transwell assay. Its ability to diminish the activity of matrix metalloproteinase (MMP) was demonstrated by zymographic assay. Our data showed 5GG could diminish the activity of MMP-9 more than that of MMP-2. The effect on MMP-9 was elicited in a dose- and time-dependent manner, with IC50 of 15 microM. Next, we analyzed the amounts of MMP-9 and MMP-2 protein in conditioned media and in the cells. The data indicated MMP-9 proteins were also suppressed by 5GG in the same manner. In accordance with these data above, the results of reverse transcriptase polymerase chain reaction (RT-PCR) and Northern blot analysis showed a reduced level of MMP-9 mRNA. Furthermore, we studied transcription factor binding to MMP-2 and MMP-9 promoter regions by electrophoretic mobility shift assay (EMSA) in the nucleus. The results suggested that the transcription factor binding activities of Activator protein-1 (AP-1) and Sp-1 sites was mainly down-regulated by 5GG in the concentration range of 5-15 microM, but not that of nuclear factor kappaB (NF-kappaB), polioma enhancer activator 3 (PEA-3), and Activator protein-2 (AP-2) sites. The Western blot analysis of AP-1 nuclear protein showed a reduced level of c-Jun but not of c-Fos. In addition, the expression of Sp-1 and c-Jun protein was also suppressed. To elucidate whether the transcriptional activity of AP-1 or Sp-1 sites is more important, we transfected MMP-9/luciferase reporter vector, under MMP-9 promoter control, into the cells. We found that a decreased transcriptional activity of AP-1 sites is sufficient to reduce MMP-9 promoter activity. These results lead us to conclude that 5GG restricts the invasive ability of B16F10 mouse melanoma cells by reducing MMP-9 activity, by suppressing the transcriptional activity of AP-1 sites and the expression of c-Jun protein. The result may provide a potential mechanism for 5GG in cancer chemopreventive action.
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PMID:Penta-O-galloyl-beta-D-glucose inhibits the invasion of mouse melanoma by suppressing metalloproteinase-9 through down-regulation of activator protein-1. 1239 98

The production of matrix metalloproteinases (MMP) by UV-irradiated skin fibroblasts and the degradation of the extracellular matrix by these enzymes is known as one of the main causes of photoaging. Recently, the Fisher group showed that MMP expression is mainly regulated by members of the mitogen-activated protein kinase family such as extracellular signal-regulated kinase, c-Jun amino-terminal kinase, and p38, each of which forms a signaling pathway. In this work, we initially examined the effect of nitric oxide (NO) and nitric oxide synthase (NOS) inhibitors on the production of MMP-1 and MMP-2 by human dermal fibroblasts (HDF). NO is a multifunctional messenger molecule generated from L-arginine and can activate guanylate cyclase to increase cGMP. We found that treatment of HDF with an NO donor, sodium nitroprusside (50 microM), enhanced the expression of MMP-1 and -2 by 153% and 243%, respectively, and treatment by 8-Br-cGMP enhanced MMP-1 and -2 expression by 137% and 254%, respectively. When UV-irradiated HDF was treated with NOS inhibitors such as aminoguanidine (AG) and baicalein (BAC), there resulted a decrease in MMP production. When 20 microM of BAC was added in the culture media of UV-irradiated HDF, only 40% of MMP-1 and 42% of MMP-2 was produced, compared to the case without BAC. Taken together, we concluded that the production of MMP-1 and -2 by UV-irradiated HDF is regulated through the signaling pathway involving NO and that it can be downregulated using NOS inhibitors.
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PMID:Inhibition of matrix metalloproteinase-1 and -2 expression using nitric oxide synthase inhibitors in UV-irradiated human dermal fibroblasts. 1285 22

Activation or suppression of intracellular signaling via the mitogen-activated protein kinase (MAPK) family has been linked to expression of matrix metalloproteinases (MMP) in experimental models, but this association has not been demonstrated in clinical material. The objective of this study was to investigate the possible association between expression and activity of MMP, expression of the MMP inducer EMMPRIN, and the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK) and high osmolarity glycerol response kinase (p38) in effusions from patients diagnosed with serous ovarian carcinoma. MAPK level and activity were studied in 55 effusions using immunoblotting. MMP-1, MMP-2, MMP-9 and EMMPRIN expression was studied using immunocytochemistry (ICC) and mRNA in situ hybridization (ISH). The gelatinolytic activity of MMP-2 and MMP-9 was measured by zymography. ERK and phospho-ERK (p-ERK) were detected in 54/55 (98%) and 50/55 (91%) specimens, respectively. JNK and p-JNK were detected in 53/55 (96%) and 38/55 (69%) specimens, respectively. p38 was expressed in 54/55 (98%) specimens, and its phosphorylated form was found in 51/55 (92%). MMP-2 mRNA expression (P = 0.048), protein expression (P = 0.046) and gelatinolytic activity (P = 0.039) correlated with ERK phosphorylative activity. MMP-2 activity also correlated with p38 activity (P = 0.017). MMP-9 protein expression correlated with phosphorylation of p38 (P = 0.046), but enzyme activity showed inverse relationship with both p-ERK (P = 0.05) and p-p38 (P = 0.033) expression. EMMPRIN expression correlated with MMP-1 (P < 0.001), MMP-2 (P = 0.042) and MMP-9 (P = 0.029) expression, as well as with ERK activity (P = 0.001). Our results present the first evidence of a possible link between MAPK signaling and MMP expression and activity in vivo. These data may expand our understanding regarding the mechanisms by which MMP synthesis is regulated in effusions and possibly affect treatment strategies for this form of malignancy.
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PMID:Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): co-expression in metastatic serous ovarian carcinoma. 1466 93

Retinoic acid (RA) and sodium butyrate (NaB) have been implicated in the regulation of growth and differentiation in various cancer cells. To produce an agent with the properties of both RA and NaB, a butyryl aminophenyl ester of RA (4-BPRE) was synthesized. The agent was compared with an aminophenyl ester devoid of the butyryl group (4-APRE) for antitumor potential in vitro. Like RA, 4-hydroxyphenyl retinamide (4-HPR) and 4-APRE, 4-BPRE was an active ligand for all three subtypes of RAR, but not for RXR, as determined by transcription assays in COS-1 cells. In addition, regardless of the butyryl group, 4-BPRE actively suppressed c-Jun transcriptional activity, which may result in reduced expression of matrix metalloproteinases (MMP-1 and MMP-2), and effectively inhibited HCT116 cell invasion into Matrigel. In these respects, 4-BPRE is similar to 4-APRE, and even to RA and 4-HPR. However, our results showed that in HCT116 colon and A549 lung cancer cells, 4-BPRE was much more cytotoxic than RA and 4-APRE, and was also more cytotoxic than 4-HPR, which is the most cytotoxic retinoid derivative under clinical investigation. Subsequent assays using DAPI staining, DNA fragmentation, and FACS analysis suggested that the cytotoxic effect of 4-BPRE is mediated by apoptosis in HCT116 cells. Moreover, 4-BPRE inhibited histone deacetylase (HDAC) activity to some degree, although inhibition was less than that induced by the known HDAC inhibitors TSA and NaB. These results suggest that 4-BPRE could be a promising antitumor retinoid with both NaB activity and RA function.
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PMID:In vitro antitumor potential of 4-BPRE, a butyryl aminophenyl ester of retinoic acid: role of the butyryl group. 1476 28

Carnosol, a constant constituent of Rosmarinus officinalis extracts, is a phenolic diterpene shown to have antioxidant and anticarcinogen properties. In our studies, carnosol inhibited the invasion of highly metastatic mouse melanoma B16/F10 cells in vitro. First, the antimetastatic potentials of carnosol were examined by soft agar colony formation assay. Second, carnosol dose-dependently inhibited B16/F10 cell migration and invasion by in vitro transwell assay. Third, the decreasing activity of metalloproteinase was observed by zymographic assay. The result revealed that the treatment of carnosol could diminish the activity of MMP-9 more than MMP-2. Next, we analyzed the amounts of MMP-9 and MMP-2 proteins in the cells. The data indicated MMP-9 protein was also suppressed by carnosol in the same manner. In accordance with the above data, the results of reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed a reduced level of MMP-9 mRNA. Furthermore, carnosol significantly inhibited the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, AKT, p38, JNK and inhibition of activation of transcription factors NFkappa-B and c-Jun. These results lead us to conclude that carnosol could restrict the invasive ability of B16/F10 mouse melanoma cells by reducing MMP-9 expression and activity through suppressing (ERK) 1/2, AKT, p38, and JNK signaling pathway and inhibition of NF-kappaB and AP-1 binding activity. Taken together, these results indicate that carnosol targets MMP-mediated cellular events in cancer cells and provides a new mechanism for its anticancer activity.
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PMID:Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappa B and c-Jun. 1562 74

Colorectal carcinoma is a leading cause of human mortality due to its high metastatic ability. Because the activation of matrix metalloproteinases (MMP) is a key factor in the metastatic process, agents with the ability to inhibit MMP activity have potential in the treatment of colorectal carcinoma. In the present study, among 36 flavonoids examined, myricetin was found to be the most potent inhibitor of MMP-2 enzyme activity in COLO 205 cells (IC50 = 7.82 micromol/L). Myricetin inhibition of MMP-2 enzyme activity was also found in the human colorectal carcinoma cell lines COLO 320HSR, COLO 320DM, HT 29, and COLO 205-X (IC50 = 11.18, 11.56, 13.25, and 23.51 micromol/L, respectively). In contrast, no inhibitory effect of MMP-2 protein expression or enzyme activity was observed in myricitrin (myricetin-3-rhamnoside)-treated cells. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated COLO 205 cells, an increase in MMP-2 protein expression and enzyme activity, as well as of protein kinase C (PKC) alpha protein translocation, extracellular signal-regulated kinase (ERK) 1/2 protein phosphorylation, and c-Jun protein expression was observed. ERK inhibitor (PD98059) and PKC inhibitors (GF-109203X and H-7), but not p38 inhibitor (SB203580) or c-jun-NH2-kinase inhibitor (SP600125), significantly inhibited TPA-induced MMP-2 protein expression, with reduced ERK phosphorylation and c-Jun protein expression. Addition of myricetin but not myricitrin suppressed TPA-induced MMP-2 protein expression in COLO 205 cells by blocking the TPA-induced events, including translocation of PKCalpha from cytosol to membrane, phosphorylation of ERK1/2 protein, and induction of c-Jun protein expression. Addition of PD98059 or GF-109203X significantly enhanced the inhibitory effect of myricetin on MMP-2 enzyme activity induced by TPA. Furthermore, myricetin, but not myricitrin, suppressed TPA-induced invasion of COLO 205 cells in an in vitro invasion assay using Engelbreth-Holm-Swarm sarcoma tumor extract Matrigel-coated Transwells. Results of the present study indicate that myricetin significantly blocked both endogenous and TPA-induced MMP-2 enzyme activity by inhibiting its protein expression and enzyme activity. The blockade involved suppression of PKC translocation, ERK phosphorylation, and c-Jun protein expression.
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PMID:Myricetin inhibits matrix metalloproteinase 2 protein expression and enzyme activity in colorectal carcinoma cells. 1571 99

Matrix metalloproteinases (MMPs) play a key role in cellular invasion and growth. Recent observations on tumor tissue samples suggest that MMP activity is altered in relation to cell density. Therefore, we examined MMP(-1,-2,-3,-8,-9,-10,-11 and -13) and TIMP-1/-2 expression of well-defined cell densities in breast carcinoma cell lines with differing in vivo tumorigenicity/invasiveness (MCF-7 < MDA-MB-468 < MDA-MB-231 < MDA-MB-435). Chemoinvasion assays were performed to link the in vitro data to the in vivo behavior. In accord with previous in vivo data, expression levels of most MMPs decreased significantly with increasing cell density and correlated well with a lower in vitro invasiveness of confluent cells. Since these data suggested that cell density regulates transcription and the promoter regions of most MMPs have AP-1 transcription factor binding consensus sequences, we tested whether functional AP-1 protein was involved in the mechanism of MMP downregulation by cell density. A role for AP-1 was confirmed by over-expression of c-Jun and c-fos in confluent MDA-MB-231 cells, showing with c-Jun increased MMP-2 (5-fold), MMP-3 (1.6-fold), and MMP-9 (160-fold) expression, as well as enhanced invasive potential, while TIMP-1 expression was down-regulated (2-fold) when compared to vector controls. Our data provide clear evidence that cell density regulates major MMPs and TIMPs which are controlled by AP-1 activity so that ultimately a major regulation pathway for the control of the invasive potential of tumor cells is presented.
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PMID:Cell density-dependent regulation of matrix metalloproteinase and TIMP expression in differently tumorigenic breast cancer cell lines. 1577 90

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