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

---

Query: EC:1.14.14.3 (luciferase)
38,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protooncogene product Cbl has emerged as a negative regulator of tyrosine kinases. We have shown previously that Cbl binds to ZAP-70 through its N-terminal tyrosine kinase binding (TKB) domain. In this study, we demonstrate that overexpression of Cbl in Jurkat T cells decreases the TCR-induced phosphorylation of ZAP-70 and other cellular phosphoproteins. Coexpression of Cbl with ZAP-70 in COS cells reproduced the Cbl-induced reduction in the level of phosphorylated ZAP-70. The effect of Cbl was eliminated by the TKB-inactivating G306E mutation in Cbl as well as by a phenylalanine mutation of Tyr292 within the TKB domain binding site on ZAP-70. Notably, the oncogenic Cbl-70Z/3 mutant associated with ZAP-70, but did not reduce the levels of phosphorylated ZAP-70. Overexpression of Cbl, but not Cbl-G306E, in Jurkat T cells led to a decrease in the TCR-induced NF-AT luciferase reporter activity. Overexpression of the TKB domain itself, but not its G306E mutant, functioned in a dominant-negative manner and led to an increase in NF-AT reporter activity. Cbl-70Z/3-overexpressing cells exhibited an increase in both basal and TCR-induced NF-AT luciferase reporter activity, and this trend was reversed by the G306E mutation. Finally, by reconstituting a ZAP-70-deficient Jurkat T cell line, p116, we demonstrate that wild-type ZAP-70 is susceptible to the negative regulatory effect of Cbl, whereas the ZAP-70-Y292F mutant is resistant. Together, our results establish that the linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells.
...
PMID:The linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells. 1077 65

Brain natriuretic peptide (BNP) gene expression and chronic activation of the sympathetic nervous system are characteristics of the development of heart failure. We studied the role of the beta-adrenergic signaling pathway in regulation of the human BNP (hBNP) promoter. An hBNP promoter (-1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal cardiac myocytes, and luciferase activity was measured as an index of promoter activity. Isoproterenol (ISO), forskolin, and cAMP stimulated the promoter, and the beta(2)-antagonist ICI 118,551 abrogated the effect of ISO. In contrast, the protein kinase A (PKA) inhibitor H-89 failed to block the action of cAMP and ISO. Pertussis toxin (PT), which inactivates Galpha(i), inhibited ISO- and cAMP-stimulated hBNP promoter activity. The Src tyrosine kinase inhibitor PP1 and a dominant-negative mutant of the small G protein Rac also abolished the effect of ISO and cAMP. Finally, we studied the involvement of M-CAT-like binding sites in basal and inducible regulation of the hBNP promoter. Mutation of these elements decreased basal and cAMP-induced activity. These data suggest that beta-adrenergic regulation of hBNP is PKA independent, involves a Galpha(i)-activated pathway, and targets regulatory elements in the proximal BNP promoter.
...
PMID:Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac. 1082 15

Carbonic anhydrase II (CAII) catalyzes the reversible hydration of carbon dioxide and plays key roles in acid base homeostasis in mammals. We found that human CAII gene promoter could be activated in human cells such as HeLa and T47D cells when the CAII promoter-luciferase gene was transfected with v-Src and assayed as a reporter of the promoter activity. Kinase negative mutants of Src, in contrast, showed little activation. The activation was completely suppressed with the introduction of a dominant-negative Ras in T47D cells, while no suppression was observed in HeLa cells. Introduction of various kinds of deletions into the CAII promoter revealed two essential regions responsible for this activation. No activation, however, was observed in activated Fyn-transfected human cells or in v-Src-transfected rodent cells. These findings suggest that Src can modulate the human CAII promoter by exerting its tyrosine kinase activity in certain human cells, and that two types of Src signaling pathways, Ras-dependent and -independent, exist in a cell type dependent manner.
...
PMID:Activation of human CAII gene promoter by v-Src: existence of Ras-dependent and -independent pathways. 1086 Aug 35

Endothelin-1 (Et-1) is a vasoconstrictor peptide that plays an important role in the pathophysiology of hypertension, myocardial ischemia, and other diseases. We examined the mechanism of regulation the Et-1 mRNA expression in human microvascular endothelial cells (HMEC-1) in response to hypoxia and cobalt. To determine whether the 5'-flanking region of Et-1 gene mediate transcriptional responses to cellular hypoxia, we constructed reporter plasmids in which Et-1 5'-flanking sequences of Et-1 gene were fused to luciferase coding sequences. Constructs, which contain native Et-1 sequence 5'-AACGTGCA-3', located between -118 and -125 in the opposite orientation as the transcriptional unit, mediate transcriptional response to hypoxia and cobalt. This responsiveness was inhibited by genistein, a tyrosine kinase selective inhibitor. Both hypoxia and cobalt induced binding of HIF-1 (hypoxia inducible-1 factor) to this Et-1 hypoxia responsive element in gel shift assays. Mutation in this sequence eliminated both the hypoxia-induced HIF-1 binding and luciferase expression. Using the supershift assay we have shown that this hypoxia responsive element binds HIF-1alpha and HIF-1beta proteins. Interestingly, genistein only slightly affected HIF-1 binding. These results indicate that the Et-1 gene contains HIF-1 binding hypoxia responsive elements which mediate transcriptional responses to hypoxia and cobalt in microvascular endothelial cells. Genistein appears to inhibit this response by affecting the transcriptional activity of the HIF-1 complex, without significantly affecting its DNA-binding properties.
...
PMID:Regulation of endothelin-1 gene expression in human microvascular endothelial cells by hypoxia and cobalt: role of hypoxia responsive element. 1093 28

The immediate-early cyclooxygenase-2 (COX-2) gene encodes an inducible prostaglandin synthase enzyme which is implicated in inflammatory and proliferative diseases. COX-2 is highly induced during cell activation by various factors, including mitogens, hormones and cytokines. Since pro-inflammatory cytokine IL-1beta has been shown to induce prostaglandin E2 (PGE2) release in human gingival fibroblasts (HGF), here we analyzed the effect of IL-1beta on the expression of COX-2 and the activation of NFkappaB in HGF. Northern hybridization analysis revealed that IL-1beta (200 pg/ml) increased the expression of COX-2 mRNA in HGF. The effect of IL-1beta was abrogated by herbimycin A, a protein tyrosine kinase inhibitor, and enhanced by orthovanadate, a protein tyrosine phosphatase inhibitor. IL-1beta-induced PGE2 release was blocked by the tyrosine kinase inhibitor and increased by the tyrosine phosphatase inhibitor. The results of transient transfection assays using chimeric constructs of the human COX-2 promoter (nt -1432 approximately +59) ligated to a luciferase reporter gene indicated that IL-1beta stimulated the transcriptional activity approximately 1.5-fold. Gel mobility shift assays with a radiolabelled COX-2-NFkappaB oligonucleotide (nts-223 to-214) revealed an increase in the binding of nuclear proteins from IL-1beta-stimulated HGF. This increase of DNA-protein complex formation induced by IL-1beta was blocked by herbimycin A and another tyrosine kinase inhibitor, genistein. These results suggest that NFkappaB is an important transcription factor for IL-1beta-induced COX-2 gene expression, and is involved in inducing COX-2 gene transcription through tyrosine phosphorylation in HGF.
...
PMID:Activation of NFkappaB is necessary for IL-1beta-induced cyclooxygenase-2 (COX-2) expression in human gingival fibroblasts. 1094 8

RET finger protein (RFP) belongs to the large B-box RING finger protein family and is known to become oncogenic by fusion with RET tyrosine kinase. Although RFP is reported to be a nuclear protein that is present in the nuclear matrix, its function is largely unknown. Here we show that RFP interacts with Enhancer of Polycomb (EPC) and strongly represses the gene transcription. Yeast two-hybrid assays revealed that the coiled-coil domain of RFP was associated with the EPcA domain and the carboxyl-terminal region of EPC. In addition, both proteins were co-precipitated from the lysates of human cells and mostly colocalized in the nucleus. Using the luciferase reporter-gene assay, we found that they repress the gene transcription activity independent of the differences of enhancers and promoters used, although the repressive activity of RFP was much stronger than that of EPC. The coiled-coil domain of RFP and the carboxyl-terminal region of EPC were most important for the repressive activity of each protein, whereas the EPcA domain had the transcription activating ability that is unique as the Polycomb group protein function. These results suggested that RFP may be involved in the epigenetic gene silencing mechanism cooperating with Polycomb group proteins and that EPC is a unique molecule with both repressive and transactivating activities.
...
PMID:RET finger protein is a transcriptional repressor and interacts with enhancer of polycomb that has dual transcriptional functions. 1097 8

Several tyrosine kinase oncogenes have been associated with myeloproliferative diseases, including Bcr/Abl, Tel/Abl, Tel/Jak2, and Tel/PDGFR. One target molecule shared by these oncogenes is known to be STAT5. We generated sublines of Ba/F3 cells in which either wild-type STAT5 or a constitutively active mutant of STAT5 (STAT5-1*6) were expressed under the control of a tetracycline-inducible promoter. These cell lines were compared with a Ba/F3 cell line in which the expression of p210(Bcr/Abl) was made inducible by a similar promoter. Before induction, all cells were dependent on interleukin 3 (IL-3) for growth and survival. Both STAT5-1*6 and Bcr/Abl enhanced viability and induced proliferation in the absence of IL-3. We found that the proviability protein Bcl-X(L), but not Bcl-2, was induced by both p210(Bcr/Abl) and STAT5-1*6. Using a Bcl-X gene promoter construct fused to a luciferase complementary DNA (cDNA), both p210(Bcr/Abl) and STAT5-1*6 were shown to induce transcription of Bcl-X. The increase in transcription of the Bcl-X promoter and the increase in Bcl-X protein, due to p210(Bcr/Abl), were blocked by expression of a dominant negative STAT5 mutant. Interestingly, however, STAT5-1*6 required the continued presence of IL-3 to cause a significant increase in Bcl-X(L) protein, whereas p210(Bcr/Abl) did not need IL-3. Studies with enzyme inhibitors suggest that the extra signal supplied by IL-3 may be supplied by the PI3K pathway. Overall, these data suggest that constitutively activated STAT5 can increase viability and proliferation of Ba/F3 cells. This may contribute to, but is not likely sufficient for, the enhanced viability associated with Bcr/Abl transformation.
...
PMID:Bcr/Abl activates transcription of the Bcl-X gene through STAT5. 1097 76

Large granular lymphocyte (LGL) leukemia is characterized by the expansion of antigen-activated cytotoxic T lymphocytes. These leukemic cells are resistant to Fas-mediated apoptosis despite expressing high levels of Fas. We found that leukemic LGL from 19 patients displayed high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inhibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA binding activity. Moreover, using an antisense oligonucleotide approach to diminish STAT3 expression, we found that Fas sensitivity was restored in leukemic LGL. AG-490-induced apoptosis in leukemic LGL was independent of Bcl-xL or Bcl-2 expression. However, we found that the Bcl-2-family protein Mcl-1 was significantly reduced by AG-490 treatment. Activated STAT3 was shown to bind an SIE-related element in the murine mcl-1 promoter. Using a luciferase reporter assay, we demonstrated that v-src overexpression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones. These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia.
...
PMID:Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. 1116 Jan 59

To investigate a possible role of phosphorylation in the signal transduction pathways responsible for transcriptional regulation of drug-metabolizing enzymes, we tested seven specific tyrosine kinase inhibitors (tyrphostins) for their effects on NAD(P)H:quinone oxidoreductase-1 (NQO1) mRNA levels in mouse hepatoma Hepa-1c1c7 (Hepa-1) cells and chose to study AG879 further. The potent electrophile tert-butylhydroquinone (tBHQ) is known to activate NQO1 gene transcription via the electrophile response element (EPRE). Among the tyrphostins tested, tyrphostin AG879 was unique in preventing the accumulation of tBHQ-induced NQO1 mRNA; this effect was dependent on the AG879 dose and was also sensitive to the time when AG879 was added relative to the beginning of tBHQ treatment. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is known to activate Cyp1a1 gene transcription by way of aromatic hydrocarbon response elements (AHREs). We found that AG879 also prevents, to a lesser extent, the AHRE-mediated induction of CYP1A1 and NQO1 mRNA by dioxin. Zinc or cadmium is known to activate metallothionein (Mt1) gene transcription via the metal response element (MRE). AG879 induced MT1 mRNA, and AG879 did not block zinc- or cadmium-induced MT1 mRNA, indicating that the effects of AG879 on NQO1 or CYP1A1 mRNA levels cannot be generalized to all transcripts. Using transient transfection of EPRE-, AHRE-, or MRE-driven luciferase reporter gene constructs in Hepa-1 cells, we showed that the inhibitory effects of AG879 occurred at the level of EPRE- and AHRE-mediated transcription, but that AG879 did not affect the MRE-driven transcriptional response. These data suggest that AG879 might inhibit an unknown tyrosine kinase(s) whose activity is essential for EPRE- and AHRE-mediated trans-activation of certain mammalian genes. These results also indicate that some sharing of common signal transduction pathways might exist in the regulation of genes involved in drug metabolism that also respond to oxidative stress.
...
PMID:Tyrphostin [correction of Tryphostin] AG879, a tyrosine kinase inhibitor: prevention of transcriptional activation of the electrophile and the aromatic hydrocarbon response elements. 1116 36

Brain natriuretic peptide (BNP) gene expression accompanies cardiac hypertrophy and heart failure. The vasoconstrictor endothelin-1 (ET) may be involved in the development of these diseases. ET has also been shown to activate phospholipase A(2) (PLA(2)), and the resulting metabolites are important second messengers. We studied how ET and PLA(2) metabolites regulate BNP gene expression. The human BNP (hBNP) promoter (from -1818 to +100) coupled to a luciferase reporter gene was transferred into neonatal ventricular myocytes (NVMs), and luciferase activity was measured as an index of promoter activity. ET induced BNP mRNA in NVMs as assessed by Northern blot. It also stimulated the hBNP promoter, an effect completely inhibited by actinomycin D. To test the involvement of different PLA(2) isoforms, transfected cells were treated with various PLA(2) inhibitors before stimulation with ET. Only Ca(2+)-independent PLA(2) blockade prevented ET-stimulated hBNP promoter activity. The PLA(2) metabolite lysophosphatidic acid (LPA) also activated the hBNP promoter, but arachidonic acid itself did not. ET regulation of the hBNP promoter is pertussis toxin-sensitive. The nonreceptor tyrosine kinase Src and the small GTPase Rac mediate the effects of both ET and LPA in stimulation of the hBNP promoter. We studied the involvement of cis elements in ET-stimulated hBNP promoter activity. Deletion of BNP promoter sequences from -1818 to -408 and from -408 to -40 reduced the effect of ET by 60% and 80%, respectively. Moreover, ET-stimulated luciferase activity was reduced by 50% when the proximal GATA element was mutated. These data suggest that (1) ET activates the hBNP promoter through a transcriptional mechanism; (2) LPA, perhaps generated by iPLA(2), is involved in the effect of ET; (3) Src and Rac mediate ET and LPA stimulation of the hBNP promoter; and (4) ET regulation of the hBNP promoter targets both distal and proximal cis elements.
...
PMID:Src and Rac mediate endothelin-1 and lysophosphatidic acid stimulation of the human brain natriuretic peptide promoter. 1123 Mar 22


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---