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)

Intrinsic expression of the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) may be regulated by reactive oxygen species (ROS). A transient expression of Pgp was observed during the growth of multicellular tumor spheroids. Maximum Pgp expression occurred in tumor spheroids with a high percentage of quiescent, Ki-67-negative cells, elevated glutathione levels, increased expression of the cyclin-dependent kinase inhibitors p27Kip1 and p21WAF-1 as well as reduced ROS levels and minor activity of the mitogen-activated kinase (MAPK) members c-Jun amino-terminal kinase (JNK), extracellular signal-regulated kinase ERK1,2, and p38 MAPK. Raising intracellular ROS by depletion of glutathione with buthionine sulfoximine (BSO) or glutamine starvation resulted in down-regulation of Pgp and p27Kip1, whereas ERK1,2 and JNK were activated. Down-regulation of Pgp was furthermore observed with low concentrations of hydrogen peroxide and epidermal growth factor, indicating that ROS may regulate Pgp expression. The down-regulation of Pgp following BSO treatment was abolished by agents interfering with receptor tyrosine kinase signaling pathways, i.e. the protein kinase C inhibitors bisindolylmaleimide I (BIM-1) and Ro-31-8220, the p21ras farnesyl protein transferase inhibitor III, the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1,2 activation. ROS involved as second messengers in receptor tyrosine kinase signaling pathways may act as negative regulators of Pgp expression.
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PMID:Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. 1127 18

The Rho family of Ras-related proteins, which includes Rac1, RhoA, and Cdc42, is distinguished from other members of the Ras superfamily of small GTPases in that its members possess additional sequences positioned between beta-strand 5 and alpha-helix 4, designated the insert region. Previous studies have established the importance of an intact insert region for the transforming, but not actin cytoskeletal reorganization, activities of Cdc42 and RhoA. Similarly, the insert region was determined to be essential for Rac1-mediated mitogenesis. Additionally, an intact insert region was also determined to be required for the antiapoptotic activity of Rac1 as well as for Rac1 activation of reactive oxygen species and the NF-kappaB transcription factor. However, it has not been determined whether the insert region is important for Rac1-mediated growth transformation. In this study, we assessed the requirement for the insert region in Rac1 transformation and signaling in NIH 3T3 cells. Unexpectedly, we found that a mutant of constitutively activated Rac1 that lacked the insert region retained potent transforming activity. The insert region of Rac1 was dispensable for Rac1 stimulation of transcription from the cyclin D1 promoter and for activation of the c-Jun, NF-kappaB, and E2F-1 transcription factors but was essential for Rac1 induction of serum response factor activity. While an intact insert region was dispensable for inducing reactive oxygen species production in vivo, it was required for Rac1 induction of lamellipodia. When taken together, these results show that the insert region of Rac1 serves roles in regulating actin organization and cell growth that are distinct from those of the analogous regions of Cdc42 and RhoA and support its involvement in regulating specific downstream effector interactions.
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PMID:The insert region of Rac1 is essential for membrane ruffling but not cellular transformation. 1128 63

Exposure of neonatal rat cardiac myocytes to palmitate and glucose produces apoptosis as seen by cytochrome c release, caspase 3-like activation, DNA laddering, and poly(ADP-ribose) polymerase cleavage. The purpose of this study was to understand the role of reactive oxygen species in the initiation of programmed cell death by palmitate. We found that palmitate (but not oleate) produces inhibition of carnitine palmitoyltransferase I, accumulation of ceramide, and inhibition of electron transport complex III. These events are subsequent to cytochrome c release and loss of the mitochondrial membrane potential. No differences in H2O2 production or N-terminal c-Jun kinase phosphorylation were detected between myocytes incubated in palmitate and control myocytes (nonapoptotic) incubated in oleate. These results suggest that the palmitate-induced loss of the mitochondrial membrane potential is not associated with H2O2 synthesis and that a membrane potential is required to generate reactive oxygen species following ceramide inhibition of complex III.
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PMID:Fatty acid-induced apoptosis in neonatal cardiomyocytes: redox signaling. 1129

UV-induced melanogenesis is a well known physiological response of human skin exposed to solar radiation; however, the signaling molecules involved in the stimulation of melanogenesis in melanocytes following UV exposure remain unclear. In this study we induced melanogenesis in vitro in normal human epidermal melanocytes using a single irradiation with UVA at 1 kJ/m2 and examined the potential involvement of mitogen-activated protein kinases (MAPK) as UVA-responsive signaling molecules in those cells. UVA irradiation did not affect the proliferation of melanocytes, but it did increase tyrosinase mRNA expression, which reached a maximum level 4 hr after UVA irradiation. The amount of tyrosinase protein, as quantitated by immunoblotting, was also increased at 24 hr following UVA irradiation. Among the MAPK examined, extracellular signal-related kinase (ERK) 1/2 was phosphorylated within 15 min of UVA irradiation, but no such phosphorylation was observed for c-Jun N-terminal kinases (JNK) or p38. Accordingly, the activity of ERK1/2 was also increased shortly after UVA irradiation. These responses of ERK1/2 to UVA irradiation were markedly inhibited when cells were pre-treated with N-acetyl-L-cysteine, an antioxidant, or with suramin, a tyrosine kinase receptor inhibitor. The formation of (6-4)photoproducts or cyclobutane pyrimidine dimers was not detected in cellular DNA after UVA irradiation. These findings suggest that a single UVA irradiation-induced melanogenesis is associated with the activation of ERK1/2 by upstream signals that originate from reactive oxygen species or from activated tyrosine kinase receptors, but not from damaged DNA.
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PMID:Possible involvement of ERK 1/2 in UVA-induced melanogenesis in cultured normal human epidermal melanocytes. 1131 Jul 89

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.
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PMID:Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. 1137 53

Photodynamic therapy (PDT) is being used clinically for the treatment of skin cancers. One concept of delivering the employed photosensitizer directly to target cells is to stimulate cellular synthesis of sensitizers such as porphyrins. ALA (5-aminolevulinate) is applied as a precursor of porphyrins which then serve as endogenous photosensitizers. Upon irradiation, reactive oxygen species, predominantly singlet oxygen, are generated, leading to cell death. ALA-PDT using red light (550-750 nm) is known to lead to the activation of stress kinases, such as c-Jun-N-terminal kinase and p38. These kinases are also activated by UVA (320-400 nm), whose biological effects are mediated in part by singlet oxygen. In the present study, the efficiency of a combination of both treatment strategies, ALA-PDT and UVA, in cytotoxicity and activation of stress kinases was investigated taking human skin fibroblasts as a model. Compared with the commonly used ALA-PDT with red light (LD(50) = 13.5 J/cm(2)), UVA-ALA-PDT was 40-fold more potent in killing cultured human skin fibroblasts (LD(50) = 0.35 J/cm(2)) and still 10-fold more potent than ALA-PDT with green light (LD(50) = 4.5 J/cm(2)). Its toxicity relied on the formation of singlet oxygen, as was shown employing modulators of singlet oxygen lifetime. In line with these data, strong activation of the stress kinase p38 was obtained in ALA-pretreated cells irradiated with UVA at doses two orders of magnitude lower than necessary for a comparable activation of p38 by UVA in control cells. Taken together, these data suggest UVA-ALA-PDT as a potentially interesting new approach in the photodynamic treatment of skin diseases.
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PMID:High efficiency of 5-aminolevulinate-photodynamic treatment using UVA irradiation. 1137 93

Arsenic trioxide (As2O3) induces clinical remission of patients with acute promyelocytic leukemia. As a novel anticancer agent for treatment of solid cancers, As2O3 is promising, but no in vivo experimental investigations of its efficacy on solid cancers have been done at clinically obtained concentrations. In addition, the cell death mechanism of As2O3 has yet to be clarified, especially in solid cancers. In this study, human androgen-independent prostate cancer cell lines, PC-3, DU-145, and TSU-PR1 were examined as cellular models for As2O3 treatment, and As2O3-induced cell death and inhibition of cell growth and colony formation were evaluated. The involvement of p38, c-Jun NH2-terminal kinase (JNK), caspase-3, and reactive oxygen species (ROS) were investigated in As2O3-induced cell death. Finally, As2O3 was administered to severe combined immunodeficient mice inoculated orthotopically with PC-3 cells to estimate in vivo efficacy. In all three of the cell lines, at high concentrations, As2O3 induced apoptosis and, at low concentrations, growth inhibition. As2O3 activated p38, JNK, and caspase-3 dose dependently. Treatment with the p38 inhibitor and over-expression of dominant-negative JNK did not guard against As2O3-induced cell death. In contrast with partial protection by the caspase-3 inhibitor, the antioxidant N-acetyl-L-cysteine gave marked protection from As2O3-induced apoptosis and eliminated the activation of p38, JNK, and caspase-3, and the generation of ROS. The orthotopic murine metastasis model showed in vivo tumor growth inhibition in orthotopic and metastatic lesions with no signs of toxicity. This study establishes that As2O3 provides a novel, safe approach for treatment of androgen-independent prostate cancer. Generation of ROS as a therapeutic target for the potentiation of As2O3-induced apoptosis also was shown.
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PMID:Tumor growth inhibition by arsenic trioxide (As2O3) in the orthotopic metastasis model of androgen-independent prostate cancer. 1145 88

Manganese superoxide dismutase (MnSOD) is a nuclear encoded primary antioxidant enzyme localized in mitochondria. Because expression of MnSOD plays a major role in maintaining cellular redox status and reactive oxygen species are known to play a role in signal transduction and carcinogenesis, we investigated the role of MnSOD in the development of cancer using a two-stage [7,12-dimethylbenz(a)-anthracene plus 12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis model. Female transgenic mice expressing the human MnSOD gene in the skin and their nontransgenic counterparts were used in this study. Pathological examination demonstrated significant reduction of papilloma formation in transgenic mice. Quantitative analysis of 4-hydroxy-2-nonenal-modified proteins showed greater accumulation of oxidative damage products in nontransgenic compared with transgenic mice, and this oxidative damage was demonstrated to be present in both mitochondria and nucleus. TPA increased activator protein-1 (AP-1) binding activity within 6 h in nontransgenic mice, but increased AP-1 binding activity was delayed in the transgenic mice. Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families. Overexpression of MnSOD selectively inhibited the TPA-induced activation of protein kinase Cepsilon and prevented subsequent activation of c-Jun NH(2)-terminal kinase in response to TPA. Overall, these results indicate that MnSOD regulates both cellular redox status and selectively modulates PKCepsilon signaling, thereby delaying AP-1 activation and inhibiting tumor promotion, resulting in reduction of tumors in MnSOD transgenic mice.
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PMID:Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. 1150 57

Hepatocyte growth factor (HGF), a multifunctional cytokine of mesenchymal origin, activates the DNA binding of hypoxia inducible factor-1 (HIF-1) in the HepG2 cell line: the activated complex contained the inducible alpha subunit. An increased expression of HIF-1alpha (mRNA and nuclear protein levels) was observed. To investigate the molecular basis of the HIF-1 response under this non-hypoxic condition, we evaluated first the expression of putative target genes. We found a time-dependent increase in steady-state mRNA levels of heme oxygenase and urokinase plasminogen activator at 4 h, followed by that of urokinase receptor at 10 h. The enhanced expression of these genes might confer the invasive phenotype, since HGF is a proliferative and scatter factor. Second, we examined some aspects of HIF-1 activity regulation in HGF-treated cells with the following findings: (i) the activation of HIF-1 DNA binding was prevented by proteasome blockade, probably because stabilization of the cytosolic alpha-subunit protein level is not sufficient to generate a functional form: also under these conditions nuclear protein level of HIF-1alpha did not increase; (ii) N-acetylcysteine, a free radical scavenger, strongly decreased HIF-1 activation suggesting a role of reactive oxygen species in this process; (iii) the thiol reducing agent dithiothreitol was ineffective. Third, consistent with these data, N-acetylcysteine reduced the stimulatory effect of HGF on stress kinase activities, while p42/44 mitogen activated kinase (MAPK) was unmodified, suggesting an involvement of c-Jun-N-terminal kinase (JNK) and p38 MAPK in HIF-1 activation. Finally, LY 294002 induced the blockade of phosphatidylinositol 3-kinase (PI3K), one of the principal transducers of HGF/Met receptor signalling, prevented the enhancement of HIF-1 DNA binding and JNK activity, but the inhibition of p42/44 MAPK phosphorylation with PD 98059 was ineffective. In conclusion, we suggest that HGF triggers a signal transduction cascade involving PI3K and ultimately activates HIF-1.
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PMID:Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. 1153 56

The mechanism of cardioprotection with red wine consumption was studied by examining the antideath signaling cascade of one of the principle components of red wine, proanthocyanidins. Grape seed proanthocyanidin extract (GSPE) was administered orally (100 mg/kg/d) supplemented with regular diet for 3 weeks to a group of rats while the other group was given the regular diet only for the same period of time. After 3 weeks, rats were sacrificed, hearts excised, and perfused via Langendorff mode. After stabilization, hearts were perfused in the working mode for baseline measurement of contractile function. Hearts were then made globally ischemic for 30 min followed by 2 h of reperfusion. Contractile function was continuously monitored during reperfusion, and free radical production was examined by electron spin resonance (ESR) technique. Cardiomyocyte apoptosis was examined by TUNEL staining in conjunction with an antibody against myocin heavy chain to specifically detect myocytes. Induction of JNK-1 and c-fos proteins was studied by Western blot analysis using respective antibodies followed by densitometric scanning. The results indicated significant induction of JNK-1 and c-fos proteins in the ischemic/reperfused myocardium, which was inhibited by the proanthocyanidin extract. In concert, GSPE significantly reduced the appearance of apoptotic cardiomyocytes in the ischemic/reperfused hearts. GSPE also significantly reduced the appearance of the reactive oxygen species in the hearts. Improved postischemic contractile recovery was achieved with GSPE suggesting its cardioprotective action. The results of this study indicated that GSPE functioned as an in vivo antioxidant, and its cardioprotective properties may be at least partially attributed to its ability to block antideath signal through the inhibition of proapoptotic transcription factor and gene, JNK-1 and c-Jun.
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PMID:Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and C-JUN. 1155 10


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