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)

The induction of the AP-1 transcription factor has been ascribed to the early events leading to T lymphocyte activation. We have examined the possibility that stimulation of phospholipase D (PLD) may regulate activation of transcription factor AP-1 in human T cells by transfecting human T lymphocyte Jurkat cells with a plasmid containing an AP-1 enhancer element and a chloramphenicol acetyltransferase reporter gene. We have detected activatable PLD in Jurkat cells, and we have found that addition of phosphatidic acid (PA), the physiologic product of PLD action on phospholipids, is rapidly incorporated into Jurkat cells and leads to activation of transcription factor AP-1. Treatment of Jurkat cells with anti-CD3 mAb activated both PLD and transcription factor AP-1. Wortmannin, an inhibitor of receptor-coupled PLD activation, blocked the anti-CD3-induced increases in both PLD activity and AP-1 enhancer activity. We found a good correlation in the transfected cells between PLD activation and induction of AP-1 enhancer activity under different experimental conditions. Furthermore, ethanol, an inhibitor of the PLD pathway, blocked the anti-CD3-stimulated AP-1 enhancer activity. However, this anti-CD3-mediated response was not inhibited by neomycin, an inhibitor of phosphoinositide hydrolysis. The increases in AP-1 enhancer activity induced by PA or anti-CD3 mAb were efficiently abrogated by the presence of propranolol, an inhibitor of PA phosphohydrolase and protein kinase C (PKC). Furthermore, the PA- and the anti-CD3-induced increases in AP-1 enhancer activity were blocked by the presence of PKC inhibitors or by PKC down-regulation. These data indicate that PLD stimulation can activate the transcription factor AP-1 in T lymphocytes, and suggest that the induction of AP-1 enhancer factor activity by PA is mediated via PKC stimulation, either through a direct activating effect of PA or through PA-derived diacylglycerol formation. These data also provide evidence for a role of PLD-derived lipids in the induction of AP-1 enhancer activity resulting from stimulation of the TCR/CD3 complex, suggesting that increased PLD activity can play an important role in T lymphocyte activation.
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PMID:Involvement of phospholipase D in the activation of transcription factor AP-1 in human T lymphoid Jurkat cells. 807 60

Bryostatin 1, a macrocyclic lactone, has undergone phase I trials as an anticancer agent. Because of the lipid solubility of this compound it must be delivered either in ethanol or in a PET formulation. During the trial, these vehicles caused a large number of treatment-related side effects. We have synthesized the triethanolamine salt of 26-succinylbryostatin 1 and find that this compound is approx. 100-fold more water soluble than bryostatin 1. Because of the potential for clinical use, we have evaluated the biologic activity of this compound. We find that in a concentration-dependent manner 26-succinylbryostatin 1 is capable of activating protein kinase C (PKC) in vitro and displacing [3H]PDBu from PKC. However, at all concentrations tested the activity was less than the parent compound bryostatin 1. Addition of bryostatin 1 but not 26-succinylbryostatin 1 to U937 leukemic cells in culture stimulated a drop in cytosolic PKC, secondary to translocation of PKC to the membrane. Although 26-succinylbryostatin 1 did not stimulate a drop in the cytosolic levels of PKC, addition to U937 cells activated transcription from an AP-1 enhancer construct and c-Jun protein phosphorylation in a similar fashion to bryostatin 1 and differentiation of U937 cells. Unlike bryostatin 1, 26-succinylbryostatin 1 was unable to cause aggregation of human platelets. Although injection of bryostatin-1 into mice carrying B16 melanoma inhibits tumor growth, there was no significant inhibition of melanoma growth when identical doses of 26-succinylbryostatin 1 were injected. Therefore, 26-succinylbryostatin 1 shares some but not all of the pharmacologic properities of bryostatin 1. This compound can activate protein phosphorylation without lowering cytosolic levels of PKC.
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PMID:Biological activity of 26-succinylbryostatin 1. 870 88

The expression of the proteins (C-FOS and C-JUN) encoded by the immediate early genes c-fos and c-jun was investigated in the brains of rats undergoing ethanol withdrawal. Both proteins were induced in the cerebral cortex, the piriform cortex, the olfactory bulb, the inferior colliculus, the granular cell layer of the cerebellum and in the brain stem, but only C-JUN was induced in the hippocampus of animals undergoing withdrawal without overt seizures. C-FOS was detected in the hippocampus only in animals with overt seizures. Maximal C-FOS expression occurred 15 hr after withdrawal while C-JUN was maximal at 24 hr. Gel-shift assays indicated the formation of AP-1 binding factors in nuclear extracts of the cerebral cortex, hippocampus and cerebellum 15 and 17 hr after withdrawal. These data reveal a complex pattern of immediate early gene expression during ethanol withdrawal, which may be associated with changes in neuronal plasticity underlying phenomena such as withdrawal kindling.
Alcohol Alcohol Suppl 1994
PMID:Gene expression during ethanol withdrawal. 897 22

Cytokines, such as TNF alpha, modulate the behavior of many cells by regulating the expression of a wide array of genes. When a cytokine binds to its receptor on the cell surface, the receptor becomes activated and activates signal transduction cascades. These cascades typically involve a series of phosphorylation reactions that lead to sequential activation of various kinases. The targets of these kinases include DNA binding proteins that regulate the transcription of target genes. The activity of DNA binding proteins, such as c-Jun and NF-kappa B, titrates the transcriptional activity of cytokine-regulated genes. Both acute and chronic alcohol consumption of ethanol increase hepatic expression of TNF alpha. After acute ethanol consumption, this is associated with increased induction of several TNF-dependent regenerative events, including the activation of c-Jun and increased binding activity of NF-kappa B. However, chronic consumption of ethanol appears to impede TNF alpha signaling in the liver because it attenuates the increases in c-JUN activity and NF-kappa B binding, which normally follow partial hepatectomy. These results suggest that one mechanism by which ethanol influences liver cell behavior is by influencing local expression of TNF alpha and changing the activity of TNF-regulated transcription factors.
Alcohol Clin Exp Res 1996 Dec
PMID:Alcohol and cytokine-inducible transcription factors. 898 16

The DNA-binding activities of AP-1 and Egr proteins were investigated in nuclear extracts of rat brain regions during ethanol withdrawal. Both DNA-binding activities were transiently elevated in the hippocampus and cerebellum 16 h after withdrawal. In the cerebral cortex, AP-1 and Egr DNA-binding activities increased at 16 h and persisted until 32 and 72 h, respectively. The AP-1 DNA-binding activities in all regions at all times after withdrawal were composed of FosB, c-Jun, JunB, and JunD. c-Fos was detected at all times in the cerebral cortex, at 16 h only in the hippocampus, and from 16 to 72 h in the cerebellum. Withdrawal severity did not affect the composition of the AP-1 DNA-binding activities. Two Egr DNA-binding activities were present in the cortex and hippocampus. The faster-migrating complex predominated in hippocampus, and only the slower-migrating complex (identified as Egr-1) was present in the cerebellum. The increase in DNA-binding activity of immediate early gene-encoded transcription factors supports their proposed role in initiating a cascade of altered gene expression underlying the long-term neuronal response to ethanol withdrawal.
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PMID:AP-1 and Egr DNA-binding activities are increased in rat brain during ethanol withdrawal. 920 24

Previous studies suggest that estrogen receptor-positive (ER+) breast cancer cells acquire resistance to transforming growth factor-beta (TGF-beta) because of reduced expression levels of TGF-beta receptor type II (RII). We now report that treatment of ER+ breast cancer cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-2'-dC) leads to accumulation of RII transcript and protein in three different cell lines. RII induction restored TGF-beta response in MCF-7L breast cancer cells as indicated by the enhanced activity of a TGF-beta responsive promoter-reporter construct (p3TP-Lux). A transiently transfected RII promoter-reporter element (RII-chloramphenicol acetyltransferase) showed an increase in activity in the 5-aza-2'-dC-treated MCF-7L cells compared with untreated cells, suggesting the activation of a transactivator of RII transcription. Using electrophoretic mobility shift assays, the enhanced binding of proteins from 5-aza-2'-dC-treated MCF-7L nuclear extracts to radiolabeled Sp1 oligonucleotides was demonstrated. An RII promoter-chloramphenicol acetyltransferase construct containing a mutation in the Sp1 site was not expressed in the 5-aza-2'-dC-treated MCF-7L cells, further demonstrating that induction of Sp1 activity by 5-aza-2'-dC in the MCF-7L cells was critical to RII expression. Northern analysis indicated that 5-aza-2'-dC treatment did not affect the Sp1 transcript levels. Western blot analysis revealed an increase of Sp1 protein in the 5-aza-2'-dC-treated MCF-7L cells, but there was no change in the c-Jun levels. Studies after cyclohexamide treatment suggested an increase in the Sp1 protein stability from the 5-aza-2'-dC-treated MCF-7L extracts compared with untreated control extracts. These results indicate that the transcriptional repression of RII in the ER+ breast cancer cells is caused by suboptimal activity of Sp1, whereas treatment with 5-aza-2'-dC stabilizes the protein thus increasing steady-state Sp1 levels and thereby leads to enhanced RII transcription and subsequent restoration of TGF-beta sensitivity.
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PMID:Induction of transforming growth factor-beta receptor type II expression in estrogen receptor-positive breast cancer cells through SP1 activation by 5-aza-2'-deoxycytidine. 963 22

Chronic ethanol intake may interfere with retinoid signal transduction by inhibiting retinoic acid synthesis and by enhancing activator protein-1 (AP-1) (c-Jun and c-Fos) expression, thereby contributing to malignant transformation. To determine the effect of ethanol on hepatic retinoid levels, retinoic acid receptors (RARs) and AP-1 (c-Jun and c-Fos) gene expression, chronic ethanol (36% of total calorie intake) pair-feeding was conducted on rats for a 1-month period. Retinoic acid, retinol, and retinyl ester concentrations in both liver and plasma were examined by using high-performance liquid chromatography (HPLC). Both retinoic acid receptor (alpha, beta, gamma) and AP-1 (c-Jun and c-Fos) expression in the rat liver were examined by using Western blot analysis. Treatment with high-dose ethanol led to a significant reduction of retinoic acid concentration in both the liver and the plasma (11- and 8.5-fold reduction, respectively), as compared with animals pair-fed an isocaloric control diet containing the same amount of vitamin A. Similar to the retinoic acid reductions, both retinol and retinyl palmitate levels in the livers of the alcohol-fed group decreased significantly, but in smaller fold reduction (6.5- and 2.6-fold reduction, respectively). Ethanol did not modulate the expression of RARalpha, -beta, and -gamma genes in the liver. However, chronic alcohol feeding enhanced AP-1 (c-Jun and c-Fos) expression by 7- to 8-fold, as compared with the control group. These data suggest that functional downregulation of RARs by inhibiting biosynthesis of retinoic acid and up-regulation of AP-1 gene expression may be important mechanisms for causing malignant transformation by ethanol.
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PMID:Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver. 973 67

Chronic and excessive ethanol consumption is associated with cellular proliferation, fibrosis, cirrhosis, and cancer of the liver. The critical event in early alcohol-induced hepatic injury is an alcohol-induced activation (cell proliferation and increased fibrogenesis) of hepatic stellate cells. However, the mechanisms by which alcohol causes proliferative activation in hepatic stellate cells have not been identified. An important characteristic of alcohol-induced injury is impaired vitamin A nutritional status. The demonstration that retinoic acid is the most physiologically active derivative of vitamin A and the discovery of retinoic acid receptors provide a mechanistic basis for understanding the actions of vitamin A and alcohol on hepatic cell proliferation. Recent studies have demonstrated that chronic alcohol intake can reduce hepatic retinoic acid concentrations, diminish retinoid signaling, and enhance activator protein-1 (AP-1 (c-Jun and c-Fos)) expression in rat liver. These are the possible biochemical and molecular mechanisms whereby ethanol ingestion results in hepatic stellate cell proliferative activation and hepatic fibrogenesis.
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PMID:Chronic alcohol intake interferes with retinoid metabolism and signaling. 1007 3

This manuscript was given as a plenary lecture at the annual meeting of the Research Society on Alcoholism in July of 1999. It describes the general mechanisms by which tumor necrosis factor (TNF) alpha, an injury-related cytokine, promotes liver regeneration and then details how TNF-initiated hepatotrophic signals are inhibited by chronic ethanol consumption. There is evidence that chronic ethanol exposure impairs the TNF-dependent activation of stress-activated protein kinases and some of their targets, including the growth-stimulatory DNA binding protein, c-Jun. Ethanol exposure also prevents TNF from activating the redox-sensitive transcription factor, NF kappa B, in regenerating hepatocytes. These effects are followed by decreased hepatocyte proliferation, as well as by impaired induction of TNF-regulated survival factors, such as Bcl-xL, in the liver. Thus, chronic ethanol consumption may damage the liver by inhibiting the hepatotrophic and hepatoprotective actions of TNFalpha and other growth-regulatory cytokines.
Alcohol Clin Exp Res 1999 Sep
PMID:Cytokines and the molecular mechanisms of alcoholic liver disease. 1051 5

In this study we investigated effects of acute and chronic ethanol exposure on carbachol-induced activator protein-1 (AP-1) DNA binding in rat cerebellar granule cells. Acute ethanol application did not alter, whereas chronic ethanol exposure potentiated the carbachol-induced AP-1 DNA binding. The protein composition of the AP-1 transcription factor complex activated by carbachol stimulation of muscarinic receptors was analysed in control and chronic ethanol-exposed cells using a supershift assay with specific antibodies against c-Fos, Fos B, c-Jun, Jun B and Jun D proteins. Supershift analysis revealed that the carbachol-induced AP-1 complex was composed predominantly of Jun D and c-Fos. The composition of the AP-1 complex activated by carbachol in chronic ethanol-exposed cells did not differ from control. These findings indicate that chronic ethanol treatment can modulate carbachol-induced AP-1 DNA binding activity in cerebellar granule cells.
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PMID:Chronic ethanol enhances muscarinic receptor-mediated activator protein-1 (AP-1) DNA binding in cerebellar granule cells. 1058 35


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