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

It has been demonstrated that growth factors quiescin Q6 family was created by the fusion of the sulfhydryl oxidase fragment of the yeast essential for respiration and vegetative growth (ERV)1 prototype [an orthologue of hepatopoietin (HPO)] and thioredoxin (TRX)/disulfide isomerase domain during evolution. In this paper, our results demonstrated that two components of this composite protein, i.e., HPO and TRX, were involved in the same signal transduction and interacted physically in eukaryocyte. When HPO and TRX were cotransfected into COS7 cells, the activity of activator protein-1 (AP-1) and NF-kappaB was evidently enhanced compared with the transfection with HPO or TRX alone, at the same time, the phosphorylation of c-Jun was increased. They were colocalized in the cells. By Co-IP and GST pull-down experiments, we found that HPO could physically interact with TRX, which was also confirmed by yeast two-hybrid assay. By further investigation, we found both HPO and TRX were sensitive to cellular oxidative state. HPO dimer is in its natural state and could be reduced by dithiothreitol (DTT) in vitro and in vivo. Under the treatment of oxidants such as H(2)O(2) and diamide, the amount of HPO monomer was decreased significantly and assembled into dimer, and the free thiol in TRX was oxidized. HPO could transfer oxidizing equivalents to TRX via direct thiol-disulfide exchange in vitro, the redox state of TRX was also affected by HPO in vivo. Taken together, it was implicated that the oxidizing equivalents might flow from HPO to TRX and then to substrate protein by the dimerization of HPO, and its interaction with TRX finally activates the redox-sensitive transcription factor, suggesting a new redox signal pathway conducted by thiol-disulfide transformation in eukaryocytic cytoplasm.
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PMID:Direct association of hepatopoietin with thioredoxin constitutes a redox signal transduction in activation of AP-1/NF-kappaB. 1589 71

Hepatitis B virus X protein (HBx) has many cellular functions and is a major factor in hepatitis and hepatocellular carcinoma caused by HBV infection. A proteomic approach was used to search for HBx-interacting proteins in order to elucidate the molecular mechanism of hepatocarcinogenesis. HBx was attached to myc and flag tags (MEF tags) and expressed in 293T cells; the protein complex formed within the cells was purified and characterized by mass spectrometry. COP9 signalosome (CSN) subunits 3 and 4 were subsequently identified as HBx-interacting proteins. In addition, CSN subunit 5, Jun activation domain-binding protein 1 (Jab1), was shown to be a novel cellular target of HBx. In vivo and in vitro interactions between HBx and Jab1 were confirmed by standard immunoprecipitation and GST pull-down assays. An analysis of HBx deletion constructs showed that amino acids 30-125 of HBx were responsible for binding to Jab1. Confocal laser microscopy demonstrated that HBx was mainly localized in the cytoplasm, while Jab1 was found mainly in the nucleus and partially in the cytoplasm, and that the two proteins colocalized in the cytoplasm. The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx. In addition, the coexpression of HBx and Jab1 potentiated phosphorylation of JNK, leading to the subsequent phosphorylation of c-Jun, whereas the level of c-Jun and JNK phosphorylation induced by HBx was decreased in Jab1 knockdown cells. These results suggest that the interaction between HBx and Jab1 enhances HBx-mediated AP-1 activation.
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PMID:The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. 1624 77

The active form of the Xenopus X-box binding protein 1 (xXBP1) partially synergizes and partially antagonizes with BMP-4 signaling. xXBP1 overexpression inhibits mesoderm differentiation and formation of neural tissues. A functional knockdown promotes differentiation of lateral and dorsal mesoderm but not of ventral mesoderm and of neuroectoderm. We show that the active form of xXBP1 in gastrula and early neurula stage embryos is generated by removal of exon 4 and not by an endoribonuclease activity in the endoplasmic reticulum. The N-terminal region of xXBP1 which contains the basic leucine-zipper also contains a nuclear localization signal and both, the N-terminal as well as the C-terminal regions are required for xXBP1 function. The effects of xXBP1 are in part correlated to a regulatory loop between xXBP1 and BMP-4. xXBP1 and BMP-4 stimulate mutually the transcription of each other, but xXBP1 inhibits the BMP-4 target gene, Xvent-2. Both, in vitro and in vivo assays demonstrate that xXBP1 interacts with BMP-4 and Xvent-2B promoters. GST-pulldown assays reveal that xXBP1 can interact with c-Jun, the transcriptional co-activator p300 and with the BMP-4 responsive Smad1. On the other hand, xXBP1 also binds to the inhibitory Smads, Smad6 and Smad7, that can act as transcriptional co-repressors. Based on these data, we conclude that xXBP1 might function as an inhibitor of mesodermal and neural tissue formation by acting either as transcriptional activator or as repressor. This dual activity depends upon binding of co-factors being involved in the formation of distinct transcription complexes.
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PMID:XBP1 forms a regulatory loop with BMP-4 and suppresses mesodermal and neural differentiation in Xenopus embryos. 1627 78

It is widely accepted that the consumption of alcohol may lead to hepatic injuries such as hepatic fibrosis and cirrhosis. However, consumption of Maotai, one of the famous liquors in China, is found to have no obvious relevance with hepatic injury as ordinary white wine does in both epidemiological and histopathological studies. Present study used human hepatoma cell line Hep3B to address the mechanisms involved in the resistance of alcohol-induced hepatic injury by Maotai liquor. We found that exposure of Hep3B cells to Maotai residue without ethanol (MRWE) resulted in the increased GST A1 anti-oxidant responsive element (ARE) transcriptional expression, while MRWE treatment did not affect Nrf-2-dependent transcriptional activity. Those findings were further confirmed at all time points and doses tested, suggesting that GST A1 transcription was regulated by MRWE via an Nrf-2-independent pathway. Consistent with GST A1 induction, the phosphorylation of c-Jun, extracellular signal-regulated kinases (ERKs) and p38 kinase (p38 K), were also observed in MRWE-treated Hep3B cells. Furthermore, pretreatment of cells with either PD98059 (an inhibitor specific for MEK1/2-ERKs pathway) or SB202190 (an inhibitor specific for p38 K) led to a significant decrease in the induction of GST A1 transcriptional expression by MRWE treatment. Our results indicate that certain content in MRWE is able to induce GST A1 ARE transcriptional expression, which may provide protective effects for hepatic cells by antagonizing the oxidative stress derived from ethanol via an ERKs- and p38 K-dependent pathway.
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PMID:Essential roles of ERKs and p38K in up-regulation of GST A1 expression by Maotai content in human hepatoma cell line Hep3B. 1678 88

Stabilization of cytoplasmic beta-catenin is a hallmark of a variety of cancers. The stabilized beta-catenin is able to translocate to the nucleus, where it acts as a transcriptional activator of T-cell factor (TCF)-regulated genes. beta-Catenin may cross-talk with many signalling cascades to activate target genes. Whether beta-catenin cooperates with AP-1, another transcriptional complex activated during tumorigenesis is not fully clarified. We show that beta-catenin co-immunoprecipitates with c-Jun and c-Fos. GST pull-down experiments indicate a physical association of the armadillo repeat domain of beta-catenin with the DNA-binding domain of c-Jun and of the C-terminal domain of beta-catenin with the N-terminal domain of c-Fos. Promoter studies indicate that overexpression of AP-1 activates the transcription of two beta-catenin target genes, cyclin D1 and c-myc, by a mechanism independent of the AP-1 site, and fully dependent on the TCF-binding site. We further demonstrate that AP-1/beta-catenin synergism is involved during serum-induced cyclin D1 transcriptional activation. We identify a TCF-binding site on the cyclin D1 promoter which binds in vivo a complex induced by serum, containing beta-catenin, TCF4, c-Fos, c-Jun, JunB and JunD. This novel mechanism of interaction between two signalling cascades might contribute to the potentiation of malignancy.
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PMID:Physical and functional cooperation between AP-1 and beta-catenin for the regulation of TCF-dependent genes. 1714 36

Garlic organosulfur compounds are recognized as potential chemopreventive compounds. This protection is related to the induction of phase II detoxification enzymes. We previously reported that diallyl disulfide (DADS) and diallyl trisulfide (DATS) up-regulate the gene expression of the pi class of glutathione S-transferase (GSTP) and that an enhancer element named GPE I is required for this induction. In the present study, we further investigated the signal pathway involved in DADS and DATS up-regulation of this detoxification enzyme in Clone 9 cells. Cells were cultured with 25-200 micromol/L of DADS or DATS for 24 h. Western and Northern blots showed that both garlic allyl sulfides concentration dependently induced GSTP protein and mRNA expression, respectively. Changes in GST activity toward ethacrynic acid were consistent with the increase in GSTP expression (P < 0.05). Electromobility gel shift assay showed that the DNA binding activity of nuclear activator protein-1 (AP-1) is concentration-dependently increased in the presence of DADS and DATS as compared with that of the control cells. The phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), but not of p38, was stimulated in the presence of both garlic allyl sulfides. Pretreatment with SP600125 and PD98059, which are JNK and ERK inhibitors, respectively, abolished the increase in AP-1-DNA binding activity and also the induction of GSTP protein by either allyl sulfide. Our results indicate that the effectiveness of DADS and DATS on GSTP expression is likely related to the JNK-AP-1 and ERK-AP-1 signaling pathways and, thus, that DADS and DATS enhance the binding of AP-1 to GPE I.
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PMID:Diallyl disulfide and diallyl trisulfide up-regulate the expression of the pi class of glutathione S-transferase via an AP-1-dependent pathway. 1726 7

Epidermodysplasia verruciformis (EV) is a genodermatosis associated with skin cancers that results from a selective susceptibility to related human papillomaviruses (EV HPV). Invalidating mutations in either of two genes (EVER1 and EVER2) with unknown functions cause most EV cases. We report that EVER1 and EVER2 proteins form a complex and interact with the zinc transporter 1 (ZnT-1), as shown by yeast two-hybrid screening, GST pull-down, and immunoprecipitation experiments. In keratinocytes, EVER and ZnT-1 proteins do not influence intracellular zinc concentration, but do affect intracellular zinc distribution. EVER2 was found to inhibit free zinc influx to nucleoli. Keratinocytes with a mutated EVER2 grew faster than wild-type keratinocytes. In transiently and stably transfected HaCaT cells, EVER and ZnT-1 down-regulated transcription factors stimulated by zinc (MTF-1) or cytokines (c-Jun and Elk), as detected with luciferase assays. To get some insight into the control of EV HPV infection, we searched for interaction between EVER and ZnT-1 and oncoproteins of cutaneous (HPV5) and genital (HPV16) genotypes. HPV16 E5 protein binds to EVER and ZnT-1 and blocks their negative regulation. The lack of a functional E5 protein encoded by EV HPV genome may account for host restriction of these viruses.
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PMID:Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. 1815 19

The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH(2)-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function.
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PMID:Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. 1828 16

Glutathione S-transferase Pi (GSTpi) is a marker protein in many cancers and high levels are linked to drug resistance, even when the selecting drug is not a substrate. S-Glutathionylation of proteins is critical to cellular stress response, but characteristics of the forward reaction are not known. Our results show that GSTpi potentiates S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo. Mutational analysis indicated that the catalytic activity of GST is required. GSTpi is itself redox-regulated. S-Glutathionylation on Cys47 and Cys101 autoregulates GSTpi, breaks ligand binding interactions with c-Jun NH2-terminal kinase (JNK), and causes GSTpi multimer formation, all critical to stress response. Catalysis of S-glutathionylation at low pK cysteines in proteins is a novel property for GSTpi and may be a cause for its abundance in tumors and cells resistant to a range of mechanistically unrelated anticancer drugs.
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PMID:Novel role for glutathione S-transferase pi. Regulator of protein S-Glutathionylation following oxidative and nitrosative stress. 1899 Jun 98

Hemorrhagic cystitis and diffuse inflammation of the bladder, common side effects of cyclophosphamide (CY) treatment, have been linked to the generation of acrolein derived from CY metabolism. Metabolic removal of acrolein involves multiple pathways, which include reduction, oxidation, and conjugation with glutathione. Herein, we tested the hypothesis that glutathione S-transferase P (GSTP), the GST isoform that displays high catalytic efficiency with acrolein, protects against CY-induced urotoxicity by detoxifying acrolein. Treatment of wild-type (WT) and mGstP1/P2 null (GSTP-null) mice with CY caused hemorrhagic cystitis, edema, albumin extravasation, and sloughing of bladder epithelium; however, CY-induced bladder ulcerations of the lamina propria were more numerous and more severe in GSTP-null mice. CY treatment also led to greater accumulation of myeloperoxidase-positive cells and specific protein-acrolein adducts in the bladder of GSTP-null than WT mice. There was no difference in hepatic microsomal production of acrolein from CY or urinary hydroxypropyl mercapturic acid output between WT and GSTP-null mice, but CY induced greater c-Jun NH(2)-terminal kinase (JNK) and c-Jun, but not extracellular signal-regulated kinase or p38, activation in GSTP-null than in WT mice. Pretreatment with mesna (2-mercaptoethane sulfonate sodium) abolished CY toxicity and JNK activation in GSTP-null mice. Taken together, these data support the view that GSTP prevents CY-induced bladder toxicity, in part by detoxifying acrolein. Because polymorphisms in human GSTP gene code for protein variants differing significantly in their catalytic efficiency toward acrolein, it is likely that GSTP polymorphisms influence CY urotoxicity. In addition, pretreatment with dietary or nutrient inducers of GSTP may be of use in minimizing bladder injury in patients undergoing CY therapy.
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PMID:Increased sensitivity of glutathione S-transferase P-null mice to cyclophosphamide-induced urinary bladder toxicity. 1969 94


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