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)

The intracellular concentration of the 27-kDa mammalian heat shock protein, HSP27, increases several-fold after heat and other metabolic stresses and is closely associated with the acquisition of thermotolerance. Posttranslational modifications may also affect the function of HSP27. Heat shock of HeLa cell cultures, or treatment with arsenite, phorbol ester, or tumor necrosis factor, caused a rapid phosphorylation of preexisting HSP27 and the appearance of three phosphorylated isoforms, HSP27 B, C, and D. Digestion with trypsin and fractionation of the peptides by reverse phase high performance liquid chromatography revealed three 32P-labeled phosphopeptides. Microsequence analysis identified peak I as Ala76-Leu77-Ser78-Arg79 and peak II as Gln80-Leu81-Ser82-Ser83-Gly84-Val85- Ser86-Glu87-Ile88-Arg89; peak III contained the undigested peptide pair Ala76-Arg89. Ser82 was the major site and Ser78 the minor site of phosphorylation. Mutant proteins with Ser78 or Ser82 altered to glycine or Ser78-Ser82 double mutants were phosphorylated to reduced extents in vivo after heat or arsenite treatment. Ser78 and Ser82 (and Ser15) occur in the sequence motif RXXS, which is recognized by ribosomal protein S6 kinase II. Mitogenic stimulation of serum-deprived, Go-arrested Chinese hamster cells with serum, thrombin, or fibroblast growth factor also stimulated phosphorylation of HSP27 Ser78 and Ser82, and mitogenic stimulation and heat shock activated protein kinase activities that phosphorylated HSP27 and protein S6 in vitro. These results suggest that HSP27 may exert phosphorylation-activated functions linked with growth signaling pathways in unstressed cells. A homeostatic function at this level could protect cells from adverse effects of signal transduction systems which may be activated inappropriately during stress.
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PMID:Human HSP27 is phosphorylated at serines 78 and 82 by heat shock and mitogen-activated kinases that recognize the same amino acid motif as S6 kinase II. 173 Jun 70

The influence of recombinant human tumor necrosis factor-alpha (TNF-alpha) and calcium ionophore A23187 on luminol- and lucigenin-dependent chemiluminescence capacity (CL) of human polymorphonuclear leukocytes (PMN) has been studied. The CL response of TNF-alpha treated PMN is amplified by lucigenin, but not luminol. TNF-alpha and A23287 synergistically induced both the luminol- and lucigenin-dependent early CL response. The combination of A23187 and activator of protein kinase C--phorbol (myristoyl-13-acetyl)--also provoked early CL response. While the combination of TNF-alpha and A23187 decreased late CL response compared to A23187 alone. The obtained results suggests that synergistic CL response of PMN induced by TNF-alpha and A23187 is connected with activation of protein kinase by TNF-alpha.
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PMID:[The activation of the early chemiluminescent response of human neutrophils by joint treatment with tumor necrosis factor (TNF-alpha) and the calcium ionophore A-23187]. 185 55

Recent investigations have identified a signal-transduction system involving sphingomyelin and derivatives. In this paradigm, sphingomyelin hydrolysis by a sphingomyelinase generates ceramide, which may be converted to the protein kinase C inhibitor sphingosine or to ceramide 1-phosphate. Ceramide may have second-messenger function because it induces epidermal growth factor receptor phosphorylation, presumably on Thr-669 in A-431 cells. The present studies describe a kinase that may mediate ceramide action. With a 19-amino acid epidermal growth factor receptor peptide containing Thr-669, a membrane-bound activity that phosphorylated the peptide was detected in A-431 cells. Activity was linearly related to ATP (0.3-300 microM) and peptide concentration (0.02-1 mg/ml), possessed a physiologic pH optimum (pH 7.0-7.4), and was Mg(2+)-dependent. Other cations--Ca2+, Mn2+, and Zn(2+)--were ineffective. Natural and synthetic ceramide induced time- and concentration-dependent enhancement of kinase activity. Ceramide (0.5 microM) increased kinase activity 2-fold by 30 s, and activity remained elevated for at least 15 min. As little as 0.001 microM ceramide was effective, and 1 microM ceramide induced maximal phosphorylation. Sphingosine was similarly effective. Because tumor necrosis factor (TNF) alpha rapidly induces sphingomyelin hydrolysis to ceramide during monocytic differentiation of HL-60 cells, its effects on kinase activity were assessed. Kinase activity was increased 1.5-fold at 5 min and 2-fold at 2 hr in membranes derived from TNF-stimulated cells. The effective concentration range was 3 pM-30 nM TNF. Exogenous ceramide induced a similar effect. In sum, these studies demonstrate the existence of an unusual Mg(2+)-dependent ceramide-activated protein kinase that may mediate some aspects of TNF-alpha function.
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PMID:Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. 194 18

Previous studies have shown that thrombomodulin (TM) on endothelial cells is down-regulated by endotoxin, interleukin-1 beta (IL-1 beta), and tumor necrosis factor (TNF). This loss of anti-coagulant potential is thought to be related to the hypercoagulable state in sepsis, inflammation, and cancer. The current studies describe up-regulation of TM in human umbilical vein endothelial cells (HUVECs) by several compounds as judged by increased surface cofactor activity, surface TM antigen, and TM mRNA levels. Surface TM activity was increased by active phorbol esters (10(-8) M, 24-48 h), analogs of cAMP (1-10 mM, 4 h), and forskolin (10(-5) M, 24-48 h). Up-regulation of TM in HUVECs by 4 beta-phorbol 12-myristate 13-acetate (PMA) and dibutyryl cAMP (dBcAMP) was due to de novo synthesis of TM protein resulting from increased TM mRNA levels. The results suggest that protein kinase C and protein kinase A may be involved in cellular regulatory mechanisms for TM expression. In addition, PMA effects on surface TM activity are biphasic, with an initial reduction followed by a significant enhancement. Hence, we propose that compounds capable of increasing intracellular cAMP concentrations in HUVECs may be useful in preventing thrombosis by increasing the anti-thrombotic properties of endothelial cells.
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PMID:Up-regulation of thrombomodulin in human umbilical vein endothelial cells in vitro. 196 58

In this study we examined by Northern blot analysis the expression of Raf-1 protooncogene in normal human peripheral blood leukocytes. Unlike thymocytes, circulating lymphocytes did not express appreciable levels of Raf-1 mRNA. In contrast, polymorphonuclear cells (PMN) had high levels of Raf-1 transcripts. Also density gradient separated monocytes showed Raf-1 mRNA but at lower levels compared to PMN. Expression of Raf-1 was constitutive inasmuch as it was not induced by the purification procedure. The half-life of Raf-1 mRNA in PMN was greater than 4 h. Functional activation of PMN and monocytes with various stimuli (phorbol esters, tumor necrosis factor, colony stimulating factors, LPS) did not affect Raf-1 expression. By contrast, density gradient purified monocytes allowed to adhere to plastic for 1 h expressed augmented levels of Raf-1. Monocytes cultivated in suspension or allowed to adhere to plastic showed an half-life of Raf-1 transcripts of, respectively, more than 4 h and less than 30 min. Circulating lymphocytes stimulated with mitogens (PHA, conA, anti-CD3 antibodies, and Staphylococcus aureus) also expressed high levels of transcripts of this protooncogene. PHA-induced transcripts in lymphocytes had an half-life greater than 4 h. The pattern of expression of Raf-1 in resting and activated leukocytes suggests that this protooncogene may play a role in expression of differentiated functions and activation of these cells.
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PMID:Differential expression of Raf-1 protooncogene in resting and activated human leukocyte populations. 202 80

Interleukin 1 (IL-1), bacterial lipopolysaccharide (LPS) and tumor necrosis factor (TNF alpha) enhance the adherence properties of endothelial cells (EC) for neutrophils (PMN). This is mediated in part by the up-regulation of Intercellular Adhesion Molecule 1 (ICAM-1) on EC. Phorbol esters, which activate protein kinase c (PKC) and enhance the adherence properties of EC for PMN also up-regulate the ICAM-1 expression on EC. We investigated the effect of PKC inhibitors on ICAM-1 expression of human umbilical vein EC (HUVEC). Staurosporine (STS) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) prevented inflammatory mediator-dependent stimulation of both ICAM-1 expression and PMN adherence by HUVEC (ID50 for STS = 2.7-2.9 microM; for H-7 = 7.6-8.8 microM). Inhibition was dose and time-dependent and was not due to HUVEC toxicity. The STS analog K252a and the H-7 analog W-7 were less potent inhibitors of ICAM-1 up-regulation and adherence promotion. Prolonged exposure of HUVEC to phorbol myristate acetate down-regulated PKC activity and inhibited subsequent ICAM-1 up-regulation by this agent and by IL-1. We conclude that inflammatory mediator induced stimulation of HUVEC expression of ICAM-1 and promotion of adherence properties are mediated in part by activation of PKC.
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PMID:Protein kinase C inhibitors block the enhanced expression of intercellular adhesion molecule-1 on endothelial cells activated by interleukin-1, lipopolysaccharide and tumor necrosis factor. 224 11

Infection of astrocytes with Newcastle disease virus stimulated the production of 1,2-diacylglycerol, and resulted in the kinase-dependent expression of mRNAs encoding tumor necrosis factor (TNF), interferon alpha and beta, and interleukin 6. The half-life of TNF mRNA was significantly decreased in the presence of protein kinase inhibitors H-7 and staurosporine, but not in the presence of HA1004. In contrast to the decay of TNF mRNA, the half-lives of other cytokine mRNAs were only minimally affected by the kinase inhibitors. These data indicated that the stability of TNF mRNA was regulated through a novel, kinase-dependent pathway.
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PMID:Protein kinase regulates tumor necrosis factor mRNA stability in virus-stimulated astrocytes. 238 40

Phorbol esters induce the human HL-60 promyelocytic cell line to differentiate along a monocytic pathway. This induction of differentiation may involve phorbol ester-induced activation of the phospholipid- and calcium-dependent protein kinase C. Bryostatin 1, a macrocyclic lactone, has been shown to compete with phorbol esters for binding to protein kinase C. We have confirmed that bryostatin 1 translocates activity of protein kinase C from the cytosolic to membrane fractions of HL-60 cells. The present results also demonstrate that bryostatin 1 (10 nmol/L) induces monocytic differentiation of HL-60 cells as determined by adherence, growth inhibition, appearance of monocyte cell surface antigens, and alpha-naphthyl acetate esterase staining. Furthermore, bryostatin 1 (10 nmol/L) downregulated c-myc expression and induced c-fos, c-fms, and tumor necrosis factor transcripts. These changes in gene expression induced by bryostatin 1 are similar to those associated with phorbol ester-induced monocytic differentiation of HL-60 cells. In contrast, exposure to a higher concentration of bryostatin 1 (100 nmol/L) had less of an effect on growth inhibition of HL-60 cells and changes in gene expression. Moreover, 100 nmol/L bryostatin 1 antagonized the cytostatic effects and adherence induced by phorbol esters. Our results thus suggest that bryostatin 1 activates HL-60 cell protein kinase C and that this effect is associated with induction of monocytic differentiation.
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PMID:Bryostatin 1 activates protein kinase C and induces monocytic differentiation of HL-60 cells. 245 68

Interleukin-6 (IL-6) is a major systemic alarm signal that indicates the occurrence of tissue damage. The IL-6 gene is induced in various cell types by serum, inflammation-associated cytokines, viruses, and second-messenger agonists. There is an overall functional similarity between IL-6 and c-fos promoters, since transfection of excess amounts of either promoter DNA into intact HeLa cells modulates the function of the heterologous promoter construct. Furthermore, the transcription regulatory factor Fos transrepresses both the IL-6 and c-fos promoters. The 115-base pair (bp) region from -225 to -111 in the IL-6 5'-flanking region, which shares nucleotide sequence similarity with the c-fos serum response (SRE) and adjacent AP-1-like (the CGTCA motif) elements, confers responsiveness to several reagents, including serum, forskolin, and phorbol ester, upon the heterologous herpesvirus thymidine kinase (TK) promoter. In gel shift assays using nuclear extracts from HeLa cells, the 115-bp IL-6 enhancer formed several complexes that (i) were increased when extracts from induced HeLa cells were used and (ii) were inhibited most efficiently by the fos E DNA fragment (-700 to -100) and by c-fos oligonucleotides containing an intact AP-1-like site (the CGTCA motif). The 23-bp oligonucleotide designated AR1 from within the IL-6 enhancer region (-173 to -151) contains a CGTCA motif and bound nuclear proteins that also associated with c-fos oligonucleotides containing either an intact SRE or AP-1-like site. A single copy of AR1 inserted upstream of the herpesvirus TK promoter rendered this heterologous promoter inducible by IL-1 alpha, tumor necrosis factor, and serum as well as by activators of the protein kinase A (forskolin) and protein kinase C (phorbol ester) signal transduction pathways. Mutations in the AP-1-like site within AR1 (CGTCA----GTTCA) decreased inducibility of the chimeric IL-6/TK/chloramphenicol acetyltransferase gene by phorbol ester and by forskolin but not by serum, IL-1 alpha, or tumor necrosis factor. These data not only show that the AR1 segment from within the IL-6 enhancer binds nuclear proteins that also bind to c-fos regulatory elements but also demonstrate that a single copy of this 23-bp element is functionally sufficient to confer responsiveness to a variety of inducers and thus define a multiple-response element.
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PMID:A multiple cytokine- and second messenger-responsive element in the enhancer of the human interleukin-6 gene: similarities with c-fos gene regulation. 251 37

Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor on U937 cells results in rapid and TNF dose-dependent phosphorylation of a cytosolic protein with an apparent molecular mass of 26,000 kDa (p26) and an isoelectric point of 5.6. Half-maximal phosphorylation of p26 was achieved at concentrations of 1.8 ng/ml and was detectable within 20 s of TNF-alpha treatment. p26 is phosphorylated exclusively at serine residues. p26 phosphorylation occurs at 37 degrees C as well as at 14 degrees C, indicating that internalization of the TNF receptor is not required for serine kinase activation. Dephosphorylation of p26 starts 10 min after TNF-induced phosphorylation, suggesting a possible regulatory function of this cytosolic protein within the post-TNF receptor signaling system. p26 is also phosphorylated upon treatment with lymphotoxin. In contrast, both interferon-gamma and lipopolysaccharide fail to induce p26 phosphorylation. Whereas phosphorylated p26 was detected in the TNF-sensitive breast cancer cell line CRL1500, other TNF-responsive tumor cell lines investigated lacked enhanced phosphorylation of p26 in response to TNF, indicating that the 26-kDa phosphoprotein (pp26) may be a cell type-specific second messenger molecule involved in TNF signal transduction in some, but not all, target cells. p26 is also phosphorylated in a subclone of U937 (U937.C27) that responds to TNF-alpha with differentiation, yet is resistant to TNF-alpha-mediated growth inhibition. In contrast, p26 is not phosphorylated in another U937 derivative (U937.G3) that is resistant to both TNF-alpha-induced growth arrest and differentiation, suggesting that pp26 may play a role in the TNF signaling pathway linked to differentiation processes rather than to growth control.
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PMID:Tumor necrosis factor signal transduction. Tissue-specific serine phosphorylation of a 26-kDa cytosolic protein. 253 51


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