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)

Although estrogen replacement therapy may improve dampened endothelial function in postmenopausal women, the associated risk of breast and ovarian cancer has limited its long-term use. Identifying effective alternative remedy with less carcinogenicity is in serious demand. This study was designed to examine the effect of the phytoestrogen alpha-zearalanol (alpha-ZAL) on homocysteine-induced endothelin-1 (ET-1) induction, reactive oxygen species (ROS) production and transcription pathways in human umbilical vein endothelial cells (HUVECs). ROS was measured by DCF fluorescent microscopy. Homocysteine-induced expression of ET-1 mRNA, ERK, pERK and c-jun/AP-1 protein was measured using RT-PCR and Western blot analysis, respectively. ET-1 secretion was determined by the enzymatic immunoassay. Transcriptional factor AP-1 expression in response to alpha-ZAL, homocysteine or both was evaluated by transient transfection assay. Our data revealed that alpha-ZAL ablated homocysteine-elicited ET-1 secretion, upregulated ET-1 mRNA and homocysteine-induced ROS accumulation without any effects by itself. alpha-ZAL also nullified homocysteine-induced increase in c-Jun/AP-1 expression/activity without eliciting any effect by itself. Collectively, our data indicated that alpha-ZAL may antagonize homocysteine-induced ET-1 gene induction, ROS accumulation, activation of ERK signaling pathway and AP-1 transcriptional factor, all of which may contribute to alpha-ZAL-induced beneficial effect on endothelial function.
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PMID:Phytoestrogen alpha-zearalanol inhibits homocysteine-induced endothelin-1 expression and oxidative stress in human umbilical vein endothelial cells. 1790 May 92

The endoplasmic reticulum (ER) has been posited as a potential anticancer target. The synthetic antitumor alkyl-lysophospholipid analogue edelfosine accumulates in the ER of solid tumor cells. This ER accumulation of the drug leads to the inhibition of phosphatidylcholine and protein synthesis, G(2)-M arrest, depletion of ER-stored Ca(2+), Bax up-regulation and activation, transcriptional factor growth arrest and DNA damage-inducible gene 153 up-regulation, caspase-4 and caspase-8 activation, and eventually to apoptosis. Edelfosine prompted ER stress apoptotic signaling, but not the survival unfolded protein response. Edelfosine also induced persistent c-Jun NH(2)-terminal kinase (JNK) activation. Gene transfer-mediated overexpression of apoptosis signal-regulating kinase 1, which plays a crucial role in ER stress, enhanced edelfosine-induced JNK activation and apoptosis. Inhibition of JNK, caspase-4, or caspase-8 activation diminished edelfosine-induced apoptosis. Edelfosine treatment led to the generation of the p20 caspase-8 cleavage fragment of BAP31, directing proapoptotic signals between the ER and the mitochondria. bax(-/-)bak(-/-) double-knockout cells fail to undergo edelfosine-induced ER-stored Ca(2+) release and apoptosis. Wild-type and bax(-/-)bak(-/-) cells showed similar patterns of phosphatidylcholine and protein synthesis inhibition, despite their differences in drug sensitivity. Thus, edelfosine-induced apoptosis is dependent on Bax/Bak-mediated ER-stored Ca(2+) release, but phosphatidylcholine and protein synthesis inhibition is not critical. Transfection-enforced expression of Bcl-X(L), which localizes specifically in mitochondria, prevented apoptosis without inhibiting ER-stored Ca(2+) release. These data reveal that edelfosine induces an ER stress response in solid tumor cells, providing novel insights into the edelfosine-mediated antitumor activity. Our data also indicate that mitochondria are indispensable for this edelfosine-induced cell death initiated by ER stress.
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PMID:Endoplasmic reticulum stress in the proapoptotic action of edelfosine in solid tumor cells. 1797 80

Biphenolic components in Magnolia obovata including magnolol and honokiol have shown several pharmacological activities such as anti-tumor, anti-oxidant and anti-inflammatory effects. Previously in cultured macrophage Raw264.7 cells and fibroblast, we found that obovatol, an active compound isolated from M. obovata inhibited NF-kappaB activity which has been known to be a significant transcriptional factor to control of cancer cell growth. We investigated here whether obovatol could inhibit NF-kappaB activity, and thereby inhibit cancer cell growth in prostate (LNCaP and PC-3) and colon cancer (SW620 and HCT116) cells. Treatment of obovatol (10, 15, 20, 25 microM) inhibits cancer cell growth in the absence or the presence of tumor necrosis factor-alpha (TNF-alpha , 10 ng/ml) and tetradecanoyl phorbol acetate (TPA 10 or 50 nM) in a concentration-dependent manner through induction of apoptotic cell death. Cytotoxic activity was not observed in normal cells with up to 50 muM obovatol. It was also found that obovatol inhibited TNF-alpha and TPA-induced transcriptional and DNA binding activities of NF-kappaB. In further study, obovatol decreased translocation p65 and p50 into nucleus via decrease of phosphorylation of IkappaB. Correlated well with the induction of apoptosis, obovatol increased the expression of the apoptotic genes; Bax, caspase-3, caspase-9, whereas inhibited expression of anti-apoptotic genes; Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP) as well as the cell proliferation marker genes; Cox-2, c-Fos, c-Jun and cyclin D1. These results suggest that obovatol inhibits prostate and colon cancer cell growth via induction of apoptotic cell death, and that inhibition of NF-kappaB may be a significant as its action mechanism.
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PMID:Growth inhibitory effects of obovatol through induction of apoptotic cell death in prostate and colon cancer by blocking of NF-kappaB. 1824 58

We have demonstrated that LPA (lysophosphatidic acid)-induced IL (interleukin)-8 secretion was partly mediated via transactivation of EGFR [EGF (epidermal growth factor) receptor] in HBEpCs (human bronchial epithelial primary cells). The present study provides evidence that LPA-induced transactivation of EGFR regulates COX (cyclo-oxygenase)-2 expression and PGE(2) [PG (prostaglandin) E(2)] release through the transcriptional factor, C/EBPbeta (CCAAT/enhancer-binding protein beta), in HBEpCs. Treatment with LPA (1 microM) stimulated COX-2 mRNA and protein expression and PGE(2) release via G(alphai)-coupled LPARs (LPA receptors). Pretreatment with inhibitors of NF-kappaB (nuclear factor-kappaB), JNK (Jun N-terminal kinase), or down-regulation of c-Jun or C/EBPbeta with specific siRNA (small interference RNA) attenuated LPA-induced COX-2 expression. Downregulation of EGFR by siRNA or pretreatment with the EGFR tyrosine kinase inhibitor, AG1478, partly attenuated LPA-induced COX-2 expression and phosphorylation of C/EBPbeta; however, neither of these factors had an effect on the NF-kappaB and JNK pathways. Furthermore, LPA-induced EGFR transactivation, phosphorylation of C/EBPbeta and COX-2 expression were attenuated by overexpression of a catalytically inactive mutant of PLD2 [PLD (phospholipase D) 2], PLD2-K758R, or by addition of myristoylated PKCzeta [PKC (protein kinase C) zeta] peptide pseudosubstrate. Overexpression of the PLD2-K758R mutant also attenuated LPA-induced phosphorylation and activation of PKCzeta. These results demonstrate that LPA induces COX-2 expression and PGE(2) production through EGFR transactivation-independent activation of transcriptional factors NF-kappaB and c-Jun, and EGFR transactivation-dependent activation of C/EBPbeta in HBEpCs. Since COX-2 and PGE(2) have been shown to be anti-inflammatory in airway inflammation, the present data suggest a modulating and protective role of LPA in regulating innate immunity and remodelling of the airways.
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PMID:Lysophosphatidic acid-induced transactivation of epidermal growth factor receptor regulates cyclo-oxygenase-2 expression and prostaglandin E(2) release via C/EBPbeta in human bronchial epithelial cells. 1829 42

Signal transduction mechanisms mediating estradiol regulatory signals in the adrenal cortex were studied in rats. The effect of estradiol benzoate treatment on corticosteroids secretion, levels of ERK1/2, JNK, p38 mitogen-activated protein kinases, transcription factors c-Jun and c-Fos in adrenal cortex were investigated. The level of ERK1/2 was increased 1.7-fold in adrenocortical tissue after injections (3 days, 100 mkg per rat) of estradiol. However, the level of p38 kinase and protein kinase JNK was not changed in these conditions. The transcription factor AP-1, which includes c-Fos and c-Jun factors, is involved in realization of estradiol signal transduction. The level of c-Fos protein raised 1.8-fold after estradiol treatment, c-Jun protein was not increased. We conclude that ERK1/2 kinase and transcriptional factor c-Fos mediate fast estrogen signal transduction in adrenocorticocytes.
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PMID:[Effect of mitogen-activated protein kinases and transcriptional factor c-Fos on estradiol signal transduction in the rat adrenocorticocytes]. 1830 31

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

The estradiol effect on the expression level of ERK1/2, JNK, p38 mitogen-activated protein kinases, c-Jun and c-Fos transcription factors in the adrenal cortex of male rats was studied. It was shown that a single corticotropin injection caused significant changes of the ERK1/2 protein kinases levels in the adrenal cortex. This index was 1.6 times higher 1 h after the injection and was decreased 6 h after the injection. The corticotropin influence on JNK level is very significant. The protein kinase JNK level was 2.4-fold increased I h after and was decreased 6 h after the injection. However, the level of p38 kinase was not changed in these conditions. The level of c-Jun transcriptional factor increased 1.7 times 1 h after corticotropin treatment and continued decreasing with the increase of time after the injection. The level of c-Fos factor increased 1.7 times only 6 h after the injection. These changes may be an important factor of activation of adrenocortical function provoked by corticotropin.
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PMID:[The influence of protein kinases ERK, JNK and nuclear transcriptional factor c-JUN on corticotropin signal transduction in adrenocortical cells]. 1895 29

The purpose of this study was to investigate the preventive effect of glycoprotein (SNL glycoprotein, 150 kDa) isolated from Solanum nigrum Linne fruits on dextran sulfate sodium (DSS, 3%)-induced colitis in A/J mice. To determine the physiological change by SNL glycoprotein, we first evaluated nitric oxide production, lactate dehydrogenase release and thiobarbituric acid reactive substances formation in the mice serum. After that, we tested the activity of inflammation-related signals such as transcriptional factor [nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1)], inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the mice colon tissues. Our results showed that SNL glycoprotein has a dose-dependent inhibitory effect on nitric oxide production, lactate dehydrogenase release, and thiobarbituric acid reactive substances formation. In the inflammation-related signal, our finding showed that SNL glycoprotein (20 mg kg(-1)) has a suppressive effect on activities of NF-kappaB (p50) and AP-1 (c-Jun), and regulates the expression of iNOS and COX-2 in the downstream of signal pathway. Taken together, the results in this study indicated that SNL glycoprotein has potential for prevention of colitis caused by DSS in A/J mice.
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PMID:Phytoglycoprotein (150 kDa) isolated from Solanum nigrum Linne has a preventive effect on dextran sodium sulfate-induced colitis in A/J mouse. 1898 4

Both MMP-2 and MMP-9 play critical roles in tumor invasion, but their productions are differentially controlled. While the promoter region of MMP-9 has the conserved proximal AP-1 binding site, that of the MMP-2 has a noncanonical AP-1 site. To assess the role of AP-1 function, we examined the effects of dominant-negative Fos (DeltaFos), BATF and siRNA against c-Jun on MMP production in v-Crk-transformed cells which have augmented production of MMP-2 and MMP-9. Suppression of AP-1 dependent transcription by conditional expression of dominant-negative Fos (DeltaFos) and BATF substantially inhibited not only MMP-9 production but also MMP-2 production. The ChIP analysis showed the direct association of AP-1 and MMP-2 promoter region. In addition, silencing of c-Jun expression by siRNA transfection suppressed MMP-2 and MMP-9 production and in vitro invasiveness. Furthermore, the invadopodia formation of v-Crk-transformed cells could be suppressed by BATF expression or c-Jun siRNA treatment. Taken together, AP-1 appears to play a critical role in the production of MMP-2 and MMP-9 and invadopodia formation of v-Crk-transformed cells.
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PMID:A role for AP-1 in matrix metalloproteinase production and invadopodia formation of v-Crk-transformed cells. 1926 64

Ginsenoside Rg3, the main constituent isolated from Panax ginseng, has been of interest for use as a cancer preventive or therapeutic agent. We investigated here whether Rg3 can inhibit the activity of NF-kappaB, a key transcriptional factor constitutively activated in colon cancer that confers cancer cell resistance to chemotherapeutic agents. To investigate whether RG3 can suppress activation of NF-kappaB, and thus inhibit cancer cell growth, we examined the susceptibility of colon cancer cells (SW620 and HCT116) to treatment with Rg3 (25, 50, 75, 100 microM) and RG3-induced activation of NF-kappaB. RG3 dose-dependently inhibited cancer cell growth through induction of apoptosis and decreased NF-kappaB activity. In a further study of compounds in colon cancer, we used half of the IC(50) dose, values in combined treatments of Rg3 (50 microM) with conventional agents - docetaxel (5 nM), paclitaxel (10 nM) cisplatin (10 microM) and doxorubicin (2 microM). Compared to treatment with Rg3 or chemotherapy alone, combined treatment was more effective (i.e., there were synergistic effects) in the inhibition of cancer cell growth and induction of apoptosis and these effects were accompanied by significant inhibition of NF-kappaB activity. NF-kappaB target gene expression of apoptotic cell death proteins (Bax, caspase-3, caspase-9) was significantly enhanced, but the expression of anti-apoptotic genes and cell proliferation marker genes (Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP), Cox-2, c-Fos, c-Jun and cyclin D1) was significantly inhibited by the combined treatment compared to Rg3 or docetaxel alone. These results indicate that ginsenoside Rg3 inhibits NF-kappaB, and enhances the susceptibility of colon cancer cells to docetaxel and other chemotherapeutics. Thus, ginsenoside Rg3 could be useful as an anti-cancer or adjuvant anti-cancer agent.
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PMID:Inhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel. 1947 91


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