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: EC:4.2.3.23 (GAS)
957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gene for the RNA-dependent eIF-2 alpha protein kinase (PKR) was isolated from mouse genomic DNA and characterized. The mouse PKR gene contains 16 exons and spans about 28 kilobase pairs. Exon 1 is untranslated; the AUG translation initiation site is located early in the second exon. Exon 16 includes the UAG translation termination site. ATTAAA polyadenylylation signal, and a putative TA rather than CA 3' cleavage site. Primer extension analysis determined one major as well as multiple minor transcription initiation sites; the major site was 159 bp upstream of the translation initiation site. The complete cDNA of mouse PKR is, therefore, 2334 bp in length excluding the 3' poly(A)+ tail. The PKR gene 5' flanking region was a functional promoter in interferon-treated, transfected cells as measured with chloramphenicol acetyltransferase as the reporter gene. Sequence analysis of the 5' flanking region disclosed numerous potential binding sites for transcription factors including both an ISRE element and a GAS element involved in interferon inducibility; Ets, Myb, MyoD, and E2F sites commonly associated with growth control regulation and differentiation; and NF-kappa B-like sites as well as sites for two types of interleukin 6-activated factors, NF-IL6 and APRF, often associated with acute-phase, immune, and inflammatory response genes.
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PMID:Mechanism of interferon action: structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase. 791

Tumor necrosis factor receptor p75 (TNF-R p75) is a 75-kDa type I transmembrane protein expressed predominantly on cells of hematopoietic lineage. TNF-R p75 belongs to the TNF receptor superfamily characterized by cysteine-rich extracellular regions composed of three to six disulfide-linked domains. In the present report we have characterized, for the first time, the complete gene structure for human TNF-R p75, which spans approximately 43 kbp. The gene consists of 10 exons (ranging from 34 base pairs to 2.5 kilobase pairs) and nine introns (343 base pairs to 19 kilobase pairs). Consensus elements for transcription factors involved in T cell development and activation were noted in the 5'-flanking region including T cell factor-1, Ikaros, AP-1, CK-2, interleukin-6 receptor E (IL-6RE), ISRE, GAS, NF-kappaB, and Sp1. The unusual (GATA)n and (GAA)(GGA) repeats found within intron 1 may prove useful for further genome analysis within the 1p36 chromosomal locus. Characterization of the human TNF-R p75 gene structure will permit further assessment of its involvement in normal hematopoietic cell development and function, autoimmune disease, and nonrandom translocations in hematopoietic malignancies.
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PMID:Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization. 870 85

Cytokine receptors activate multiple signal transduction pathways, resulting in the induction of specific target genes. We have recently identified a hematopoietic cell-specific immediate-early gene, DUB-1, that encodes a growth-regulatory deubiquitinating enzyme. The DUB-1 gene contains a 112-bp enhancer element that is specifically induced by the beta c subunit of the interleukin-3 (IL-3) receptor. To investigate the mechanism of DUB-1 induction, we examined the effects of dominant-negative forms of JAK kinases, STAT transcription factors, and Raf-1 in transient transfection assays. In Ba/F3 cells, IL-3 induced a dose-dependent activation of DUB-1-luciferase (luc) and GAS-luc reporter constructs. A dominant-negative form of JAK2 (truncated at amino acid 829) inhibited the induction of DUB-1-luc and GAS-luc by IL-3. A dominant-negative form of STAT5 (truncated at amino acid 650) inhibited the induction of GAS-luc but not DUB-1-luc. A dominant-negative form of Raf-1 inhibited the induction of DUB-1-luc but had no effect on the induction of GAS-luc by IL-3. The requirement for JAK2 in the stimulation of the DUB-1 enhancer was further supported by the suppression of DUB-1 induction in Ba/F3 cells stably expressing the dominant-negative JAK2 polypeptide. We hypothesize that IL-3 activates a JAK2/Raf-1 signaling pathway that is required for DUB-1 induction and is independent of STAT5.
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PMID:JAK2 is required for induction of the murine DUB-1 gene. 915 35

Estrogen biosynthesis in adipose tissue increases with age and obesity, and has been implicated in the development of endometrial cancer and breast cancer. In normal human adipose tissue, expression of the CYP19 gene which encodes aromatase P450, the enzyme responsible for estrogen biosynthesis, is regulated by a distal promoter, namely promoter I.4. Stimulation of expression in adipose stromal cells by members of the type 1 cytokine family, i.e. interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), is mediated via a Jak-STAT3 signaling pathway and a GAS element upstream of promoter I.4. In contrast, aromatase expression in breast adipose tissue proximal to tumor is increased three- to four-fold to the utilization of another promoter, namely promoter II, proximal to the translation initiation site. In the present report, we show that prostaglandin (PG) E2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE2 acts via EP1 and EP2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in the maximal expression of promoter II-specific CYP19 transcripts. Because PGE2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.
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PMID:Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture. 936 91

Interferons (IFNs) are potent inhibitors of cell proliferation that are used for the treatment of several haematological malignancies. The mechanisms through which IFNs exert their antiproliferative effects on target cells, however, are largely unknown. Here we show that IFN-alpha, in murine Ba/F3 cells, directly interferes with the action of the essential mitogen interleukin (IL)-3. In transiently transfected Ba/F3 cells, IFN-alpha efficiently inhibited the IL-3-stimulated expression of a luciferase reporter construct, GAS-luc, that is activated through the JAK2/STAT5 pathway. Electrophoretic mobility shift assays and Northern blot experiments, however, revealed that neither the IL-3-induced DNA binding of STAT5 nor the transcription of the STAT5-dependent genes oncostatin-M, pim-1 and c-fos were suppressed by IFN-alpha, suggesting that the diminished expression of the luciferase protein was due to a direct inhibition of IL-3-stimulated protein synthesis. This hypothesis was supported by the observation that IFN-alpha, even though it had no effect on the transcription of the c-fos gene, efficiently suppressed the IL-3-dependent expression of the c-Fos protein. Furthermore, our results indicate that IFN-alpha induced an overexpression of the double-stranded RNA-activated protein kinase (PKR), an enzyme that inhibits protein synthesis through the phosphorylation and inactivation of the eukaryotic initiation factor-2. Therefore, we hypothesize that IFN-alpha, in Ba/F3 cells, interrupts IL-3-dependent mitogenic signals, at least in part, through the suppression of protein synthesis and that induction of PKR activity may play a pivotal role in this process.
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PMID:Interferon-alpha inhibits proliferation of Ba/F3 cells by interfering with interleukin-3 action. 1057 32

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides that affect both innate and acquired immunity, down-regulate IL-12 p40 and inducible NO synthase expression in LPS/IFN-gamma-stimulated macrophages. We showed previously that VIP/PACAP inhibit NF-kappaB nuclear translocation through the stabilization of IkappaB and reduce IFN regulatory factor-1 (IRF-1) binding to the regulatory elements found in the IL-12 p40 and inducible NO synthase promoters. In this paper we studied the molecular mechanisms involved in the VIP/PACAP regulation of IRF-1 transactivating activity. Our studies indicate that the inhibition in IRF-1 binding correlates with a reduction in IRF-1 protein and mRNA in IFN-gamma-treated Raw 264.7 macrophages. In agreement with the described Janus kinase (Jak)1/Jak2/STAT1/IRF-1 activation pathway, VIP/PACAP inhibit Jak1/Jak2, STAT1 phosphorylation, and the binding of STAT1 to the GAS sequence motif in the IRF-1 promoter. The effects of VIP/PACAP are mediated through the specific VIP/PACAP receptor-1 and the cAMP/protein kinase A (PKA) transduction pathway, but not through the induction of suppressor of cytokine signaling-1 or suppressor of cytokine signaling-3. Because IFN-gamma is a major stimulator of innate immune responses in vivo, the down-regulation of IFN-gamma-induced gene expression by VIP and PACAP could represent a significant element in the regulation of the inflammatory response by endogenous neuropeptides.
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PMID:Inhibition of IFN-gamma-induced janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. 1097 15

PC12 cells were used to compare signaling pathways activated by alpha1-adrenergic receptor (AR) subtypes. PC12 cells were transfected with human alpha1A, alpha1B, or alpha1D-ARs, and subclones stably expressing receptor densities in physiological ranges isolated and characterized. Norepinephrine (NE) activated a large number of signaling pathways in transfected cells, including inositol phosphate formation, intracellular calcium, all three arms of the mitogen activated protein kinase pathways, and a number of tyrosine kinases. Activation of mitogen activated protein kinase pathways and tyrosine kinases was not blocked by chelation of intracellular calcium with BAPTA or inhibition of protein kinase C. NE also activated luciferase reporter constructs for seven different transcription factors (AP1, SRE, CRE, NFkappaB, NFAT, Stat, GAS) following transfection into alpha1A-AR expressing PC12 cells. However, similar increases in inositol phosphate formation and intracellular Ca2+ caused by purinergic P2Y2 receptor activation did not activate any of these reporters. Comparison of alpha1-AR subtypes showed that the alpha1A activated all seven reporters, the alpha1B showed smaller effects, while the alpha1D was ineffective. NE caused differentiation of alpha1A, but not alpha1B or alpha1D, -AR expressing PC12 cells similar to that caused by NGF. This NE-induced differentiation was reduced or blocked by all inhibitors tested. We conclude that alpha1-ARs activate many signaling pathways and transcriptional responses in PC12 cells, which are not linearly related to second messenger production, and which may differ for different alpha1-AR subtypes.
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PMID:Signaling pathways activated by alpha1-adrenergic receptor subtypes in PC12 cells. 1135 36

It is well established that engagement of the Type I interferon (IFN) receptor results in activation of JAKs (Janus kinases), which in turn regulate tyrosine phosphorylation of STAT proteins. Subsequently, the IFN-dependent tyrosine-phosphorylated/activated STATs translocate to the nucleus to regulate gene transcription. In addition to tyrosine phosphorylation, phosphorylation of Stat1 on serine 727 is essential for induction of its transcriptional activity, but the IFNalpha-dependent serine kinase that regulates such phosphorylation remains unknown. In the present study we provide evidence that PKC-delta, a member of the protein kinase C family of proteins, is activated during engagement of the Type I IFN receptor and associates with Stat1. Such an activation of PKC-delta appears to be critical for phosphorylation of Stat1 on serine 727, as inhibition of PKC-delta activation diminishes the IFNalpha- or IFNbeta-dependent serine phosphorylation of Stat1. In addition, treatment of cells with the PKC-delta inhibitor rottlerin or the expression of a dominant-negative PKC-delta mutant results in inhibition of IFNalpha- and IFNbeta-dependent gene transcription via ISRE or GAS elements. Interestingly, PKC-delta inhibition also blocks activation of the p38 MAP kinase, the function of which is required for IFNalpha-dependent transcriptional regulation, suggesting a dual mechanism by which this kinase participates in the generation of IFNalpha responses. Altogether, these findings indicate that PKC-delta functions as a serine kinase for Stat1 and an upstream regulator of the p38 MAP kinase and plays an important role in the induction of Type I IFN-biological responses.
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PMID:Protein kinase C-delta (PKC-delta ) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727. 1183 38

Type I interferons are pleiotropic cytokines that transduce signals via activation of multiple downstream signaling cascades, including the Jak-Stat pathway. Although the roles of Stat1 and Stat2 in Type I interferon signaling are well established, the roles that other Stat-family members play in the induction of IFN-responses remain to be defined. In previous studies, we have shown that Stat5 associates with the CrkL adapter and forms a signaling complex that binds DNA. In the present study, we provide evidence that Stat5 is phosphorylated on serines 725/730 in an IFNalpha- and IFNbeta-dependent manner, providing direct evidence that serine phosphorylation of the protein is a component of an interferon signaling cascade. Such serine phosphorylation of Stat5 is Map kinase- and PI 3(')-kinase independent, while the activation of the serine kinase that phosphorylates Stat5 is regulated by upstream tyrosine kinase activity. Using mouse embryonic fibroblasts with targeted disruption of the Stat5a and Stat5b genes, we demonstrate that full activation of Stat5 is required for Type I interferon-dependent gene transcription via GAS elements. Altogether, our data provide evidence that Stat5 plays an important role in IFN-signaling and participates in the induction of Type I IFN-dependent responses. Furthermore, our results strongly suggest that, in addition to phosphorylation on tyrosine residues, phosphorylation on serine residues exhibits regulatory effects on the transcriptional capacity of Stat5.
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PMID:Role of Stat5 in type I interferon-signaling and transcriptional regulation. 1290 72

We have previously shown that interferon-alpha (IFN-alpha) inhibits proliferation of Ba/F3 cells by interfering with the action of the mitogen interleukin-3 (IL-3) [Cell Signal 11 (1999) 769]. Here, we have characterised the role of protein kinase R (PKR), an IFN-alpha-inducible enzyme, in the mediation of IL-3-antagonistic IFN-alpha effects. Downregulation of PKR expression by antisense oligonucleotide treatment blocked IFN-alpha-induced growth inhibition. Reduction of PKR levels and overexpression of a dominant-negative PKR mutant correlated with diminished inhibitory IFN-alpha effects on the IL-3-dependent expression of a luciferase reporter construct, GAS-luc. Furthermore, increased nuclear levels of STAT1 (bound in ISGF3 complexes) were observed in PKR-depleted cells cultured with or without IFN-alpha. Together, our data indicate an essential role of PKR in the mediation of IL-3-antagonistic IFN-alpha effects on Ba/F3 cells. They also suggests that activation of STAT1, an essential mediator of IFN effects, is insufficient for growth inhibition if PKR is not expressed.
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PMID:Interferon-alpha inhibits interleukin-3-induced proliferation of Ba/F3 cells in a protein kinase R-dependent manner. 1463 87


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