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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intercellular adhesion molecule 1 (ICAM-1) (CD54) is an adhesion molecule of the immunoglobulin superfamily. The interaction between ICAM-1 on B lymphocytes and leukocyte function-associated antigen 1 on T cells plays a major role in several aspects of the immune response, including T-dependent B cell activation. While it was originally believed that ICAM-1 played a purely adhesive role, recent evidence suggests that it can itself transduce biochemical signals. We demonstrate that cross-linking of ICAM-1 results in the up-regulation of class II major histocompatibility complex, and we investigate the biochemical mechanism for the signaling role of ICAM-1. We show that cross-linking of ICAM-1 on the B lymphoma line A20 induces an increase in tyrosine phosphorylation of several cellular proteins, including the Src family kinase p53/p56(lyn). In vitro kinase assays showed that Lyn kinase was activated within 1 min after ICAM-1 cross-linking. In addition, ICAM-1 cross-linking resulted in activation of Raf-1 and mitogen-activated protein kinases, as determined by gel mobility shift. Activation of these kinases may represent important components in the cascade of signals that link ICAM-1 to various ICAM-1-elicited cellular responses. These data confirm the important role of ICAM-1 as a signaling molecule in B cell activation.
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PMID:Signaling through intercellular adhesion molecule 1 (ICAM-1) in a B cell lymphoma line. The activation of Lyn tyrosine kinase and the mitogen-activated protein kinase pathway. 908 38

We have physically mapped and cloned a 2.5-Mb chromosomal segment flanking the centromeric end of the major histocompatibility complex (MHC). We characterized in detail 27 YACs, 144 cosmids, 51 PACs, and 5 BACs, which will facilitate the complete genomic sequencing of this region of chromosome 6. The contig contains the genes encoding CSBP, p21, HSU09564 serine kinase, ZNF76, TCP-11, RPS10, HMGI(Y), BAK, and the human homolog of Tctex-7 (HSET). The GLO1 gene was mapped further centromeric in the 6p21.2-6p21.1 region toward TCTE-1. The gene order of the GLO1-HMGI(Y) segment in respect to the centromere is similar to the gene order in the mouse t-chromosome distal inversion, indicating that there is conservation in gene content but not gene order between humans and mice in this region. The close linkage of the BAK and CSBP genes to the MHC is of interest because of their possible involvement in autoimmune disease.
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PMID:Physical map of human 6p21.2-6p21.3: region flanking the centromeric end of the major histocompatibility complex. 964 38

Protein kinases are involved in signal transduction pathways and play fundamental roles in the regulation of cell functions. Here we report that the gene G11 located in the human major histocompatibility complex encodes a novel Ser/Thr protein kinase. The G11 gene products of 41.5 and 30 kDa were expressed in insect cells using the baculovirus system and transiently in the mammalian cell line COS-7. It was found that after immunoprecipitation of the G11 polypeptides from recombinant baculovirus-infected insect cell lysates or transfected COS-7 cell lysates the immunoprecipitates contained a Mn2+-dependent protein kinase activity that phosphorylated alpha-casein at Ser/Thr residues and histone at Ser residues. Furthermore, mutation of the ATP-binding site by converting the invariant lysine in the catalytic domain (amino acid 317) to a proline resulted in the complete ablation of the enzyme activity. This was consistent with the observation that the G11 polypeptide can be covalently modified by the reactive ATP analogue 5'-p-fluorosulfonylbenzoyladenosine in the absence of ATP, and that this modification is prevented in the presence of 1 mM ATP, indicating that the kinase domain of the G11 polypeptide is capable of binding ATP. Immunofluorescence staining of transfected COS-7 cells transiently expressing G11 revealed that this novel Ser/Thr protein kinase is localized predominantly in the nucleus.
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PMID:The G11 gene located in the major histocompatibility complex encodes a novel nuclear serine/threonine protein kinase. 981 91

Tissue hypoxia is intimately associated with a number of chronic inflammatory conditions of the intestine. In this study, we investigated the impact of hypoxia on the expression of a panel of inflammatory mediators by intestinal epithelia. Initial experiments revealed that epithelial (T84 cell) exposure to ambient hypoxia evoked a time-dependent induction of the proinflammatory markers tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and major histocompatibility complex (MHC) class II (37 +/- 6.1-, 7 +/- 0.8-, and 9 +/- 0.9-fold increase over normoxia, respectively, each p < 0.01). Since the gene regulatory elements for each of these molecules contains an NF-kappaB binding domain, we investigated the influence of hypoxia on NF-kappaB activation. Cellular hypoxia induced a time-dependent increase in nuclear p65, suggesting a dominant role for NF-kappaB in hypoxia-elicited induction of proinflammatory gene products. Further work, however, revealed that hypoxia does not influence epithelial intercellular adhesion molecule 1 (ICAM-1) or MHC class I, the promoters of which also contain NF-kappaB binding domains, suggesting differential responses to hypoxia. Importantly, the genes for TNF-alpha, IL-8, and MHC class II, but not ICAM-1 or MHC class I, contain cyclic AMP response element (CRE) consensus motifs. Thus, we examined the role of cAMP in the hypoxia-elicited phenotype. Hypoxia diminished CRE binding protein (CREB) expression. In parallel, T84 cell cAMP was diminished by hypoxia (83 +/- 13.2% decrease, p < 0.001), and pharmacologic inhibition of protein kinase A induced TNF-alpha and protein release (9 +/- 3.9-fold increase). Addback of cAMP resulted in reversal of hypoxia-elicited TNF-alpha release (86 +/- 3.2% inhibition with 3 mM 8-bromo-cAMP). Furthermore, overexpression of CREB but not mutated CREB by retroviral-mediated gene transfer reversed hypoxia-elicited induction of TNF-alpha defining a causal relationship between hypoxia-elicited CREB reduction and TNF-alpha induction. Such data indicate a prominent role for CREB in the hypoxia-elicited epithelial phenotype and implicate intracellular cAMP as an important second messenger in differential induction of proinflammatory mediators.
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PMID:Critical role of cAMP response element binding protein expression in hypoxia-elicited induction of epithelial tumor necrosis factor-alpha. 1038 61

The response of a cell to its external environment requires rapid and significant alteration of protein amount, localization and/or function. This regulation involves a complex combination of processes that control synthesis, localization and degradation. All of these processes must be properly regulated and are often interrelated. Intracellular proteolysis is largely accomplished by the ubiquitin-dependent system and has been shown to be required for growth control, cell cycle regulation, receptor function, development and the stress response. Substrates subject to regulated degradation by this system include cyclins and cyclin-dependent kinase inhibitors, tumor suppressors, transcription factors and cell surface receptors. In addition, proteins that are damaged by oxidation or that are improperly folded or localized are substrates whose degradation by this system often leads to antigen presentation on the surface of the cell in the context of Class I major histocompatibility complex molecules. A very large body of work in the last fifteen years has shown that degradation by this system requires the covalent attachment of a small protein called ubiquitin and that this modification serves to direct target proteins for degradation by a 26S proteolytic particle, the proteasome. Thus, the attachment of the ubiquitin domain is of vital importance in regulating normal growth and differentiation, as well as in defending against cellular damage caused by xenobiotics, environmental insults, infection and mutation. This review focuses on the role of ubiquitination in the cellular signaling pathways that deal with these external influences.
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PMID:Ubiquitin-dependent signaling: the role of ubiquitination in the response of cells to their environment. 1053 65

The superantigen staphylococcal enterotoxin B (SEB) simultaneously binds both the major histocompatibility complex (MHC) class II receptor on monocytes and the T-cell receptor (TCR) on T lymphocytes, resulting in a range of cell responses including induction of tumor necrosis factor alpha (TNF-alpha). In this study, we have used mixed cultures of human peripheral blood monocytes and lymphocytes to investigate biochemical events controlling SEB induction of TNF-alpha. TNF-alpha production induced by SEB in mixed cultures is more closely associated with T cells than with monocytes: (i) a TCR-binding-site mutant of SEB (N23F) is less active in TNF-alpha induction than an MHC class II receptor-binding-site mutant (F44R), and (ii) flow cytometric analysis indicated that SEB induced TNF-alpha production in T cells but not in monocytes. Pretreatment of cells with inhibitors of signal transduction pathways was employed to further define events in SEB-induced TNF-alpha production. Neither protein kinase A inhibitors nor two protein tyrosine kinase inhibitors altered SEB-induced TNF-alpha production. In contrast, SEB induced protein kinase C (PKC) translocation, and pretreatment of cultures with inhibitors of PKC blocked TNF-alpha induction. Alteration of levels of diacylglycerol (DAG), an activator of PKC, by treatment with inhibitors of phospholipase C or DAG kinase also altered SEB-induced TNF-alpha production. These data suggest that PKC activation plays a critical role in SEB-induced TNF-alpha production in human T cells.
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PMID:Production of tumor necrosis factor alpha in human T lymphocytes by staphylococcal enterotoxin B correlates with toxin-induced proliferation and is regulated through protein kinase C. 1056 82

The type I and II interferons (IFNs) are potent stimulators of antigen processing and presentation and are essential in antiviral immunity. IFNs upregulate the transcription of major histocompatibility complex (MHC) class I and II molecules, associated antigen-processing proteins, and induce the production of direct antiviral effector molecules such as 2',5'-oligoadenylate synthetase, double-stranded-RNA-dependent protein kinase and Mx proteins. It is increasingly evident that viruses have evolved mechanisms to globally inhibit the actions of IFNs through disruption of their signal transduction pathways. Herein, we review the ability and novel mechanisms of several diverse viruses to inhibit IFN-induced JAK/STAT signal transduction.
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PMID:Viral inhibition of interferon signal transduction. 1070 14

Prostaglandins, pleiotropic immune modulators that induce protein kinase A (PKA), inhibit gamma interferon induction of class II major histocompatibility complex (MHC) genes. We show that phosphorylation of CIITA by PKA accounts for this inhibition. Treatment with prostaglandin E or 8-bromo-cyclic AMP or transfection with PKA inhibits the activity of CIITA in both mouse and human monocytic cell lines. This inhibition is independent of other transcription factors for the class II MHC promoter. These same treatments also greatly reduced the induction of class II MHC mRNA by CIITA. PKA phosphorylation sites were identified using site-directed mutagenesis and phosphoamino acid analysis. Phosphorylation at CIITA serines 834 and 1050 accounts for the inhibitory effects of PKA on CIITA-driven class II MHC transcription. This is the first demonstration that the posttranslational modification of CIITA mediates inhibition of class II MHC transcription.
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PMID:Downregulation of CIITA function by protein kinase a (PKA)-mediated phosphorylation: mechanism of prostaglandin E, cyclic AMP, and PKA inhibition of class II major histocompatibility complex expression in monocytic lines. 1141 40

Replication-deficient adenoviruses expressing human interferon-alpha2b (HuIFN-alpha2b) or the hybrid IFN-alpha2alpha1 or those with the secretory signal deleted, whose express is driven by the alpha-fetoprotein (AFP) promoter, were constructed and characterized. Synthesis of IFN protein and secretion or intracellular retention were tested by Western blotting and immunoassay. Expression of IFN by the recombinant adenoviruses was restricted to cells that constitutively express AFP. In these cells, expression of both secreted and nonsecreted recombinant IFN resulted in inhibition of cell proliferation, resistance to viral infection, induction of major histocompatibility complex (MHC) class I expression, increased apoptosis, and activation of an IFN-stimulated response element (ISRE)-containing promoter. Also, the induction of protein kinase R (PKR), increased phosphorylation of Stat1, and accumulation of hypophosphorylated pRb were observed for both the secreted and nonsecreted IFN, suggesting that the nonsecreted IFN may act through a similar pathway. Hep3B cells, an AFP-positive line derived from a patient with hepatocellular carcinoma (HCC), were injected subcutaneously (s.c.) into athymic nude mice to generate established tumors. Intratumoral injection of recombinant adenoviruses expressing secreted as well as the nonsecreted IFN caused suppression of tumor growth. As the AFP promoter is activated in many HCC cells but is silent in normal cells, these constructs may be useful in restricting IFN effects to the tumor cells while reducing toxicity to the neighboring tissues.
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PMID:Selective expression of nonsecreted interferon by an adenoviral vector confers antiproliferative and antiviral properties and causes reduction of tumor growth in nude mice. 1144 Jun 37

Although infection of single-stranded RNA viruses can enhance expression of major histocompatibility complex (MHC) class I genes, the mechanism underlying this process remains unclear. Recent studies have indicated that exposure of non-immune cells to double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) of viral origin can directly increase the expression of MHC class I and related molecules without immune cell interaction. In this report, we show that transfection of single-stranded hepatitis A virus RNA into cultured hepatocytes results in the induction of genes for MHC class I, LMP2 and transporter for antigen processing (TAP1), in addition to the generation of viral proteins. We suggest that this stimulatory effect is due to the double-stranded RNA formed during replication of single-stranded viral RNA, and involves both double-stranded, RNA-dependent protein kinase PKR and the secretion of IFNbeta.
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PMID:Transfection of single-stranded hepatitis A virus RNA activates MHC class I pathway. 1187 45


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