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)

Undifferentiated F9 and PCC4 embryonal carcinoma (EC) cells contain low levels of AP-1 DNA binding activity. Upon differentiation induced by retinoic acid and cyclic AMP or in differentiated cell lines, AP-1 DNA binding activity can be readily detected. Minute amounts of 3T6 cells extracts, that by themselves were unable to show any binding to an AP-1 site, stimulate AP-1 DNA binding activity when added to the EC cell extracts, suggesting that components of the 3T6 extracts stimulate this DNA binding activity in F9 and PCC4 cell extracts. This enhancement of DNA binding activity requires the presence in the donor fraction (3T6 cells) of a thermostable protein(s) that possesses neither protein kinase nor phosphatase activities. The proteins responsible for stimulation in 3T6 extracts can be separated from the ones responsible for AP-1 binding by chromatography. 3T6 c-fos immunodepleted fractions are unable to activate AP-1 DNA binding activity in EC cell extracts, while c-jun depleted fractions activate normally. Moreover, in vitro translated c-fos, but not c-jun proteins, are able to stimulate binding in EC extracts. These data suggest an important role for c-fos protein in activation of a specific DNA binding transcriptional factor during cellular differentiation and provide a convenient in vitro assay for c-fos function.
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PMID:c-fos mediated stimulation of an AP-1 DNA binding activity in undifferentiated teratocarcinoma cell lines. 215 82

Early in adenovirus infection, the E1A (early region 1A) oncogene products trans-activate the other early viral transcription units, as well as some cellular promoters. The mechanism by which E1A elicits its activity is still unknown. In this report, I show that the adenovirus E2a and E3 promoters are cAMP inducible in rat pheochromocytoma PC12 cells and that this activation requires the presence of the cAMP-dependent protein kinase II. Using deletion mutants of the E2a promoter, it was found that the sequence TACGTCAT located between positions -70 and -77 is involved in both the cAMP response and the E1A trans-activation. Also, in the mutant PC12 cell line A126-2B, which lacks the cAMP-dependent protein kinase II, E1A is still able to activate E2a and E3 promoters. This suggests that E1A products may circumvent the lack of the kinase by activating an alternative signal transduction pathway, which could mimic the effect of agonists of adenylate cyclase. I propose that E1A is capable of modifying by phosphorylation, either directly or indirectly, the transcription factor that binds the ACGTCA motif. Such a factor, termed ATF (adenovirus transcription factor), has already been characterized and appears to have strong similarities to the transcriptional factor CREB (cAMP responsive element binding protein), which binds homologous sequences in cAMP responsive genes, such as somatostatin and c-fos.
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PMID:Cyclic AMP induction of early adenovirus promoters involves sequences required for E1A trans-activation. 290 26

2,3,7,8-Tetrachloro-p-dioxin (TCDD) induced a modest stimulation of nuclear protein phosphorylation in explant tissue cultures in 10 min, followed by a substantial decrease in the level of total protein phosphorylation activity in the nucleus. Curiously, this TCDD-induced decline in nuclear protein phosphorylation was accompanied by an increase in cytosolic and extranuclear protein phosphorylation activity. One of the main causes for such a decrease in the protein phosphorylation activity in the nucleus appears to be related to some increase in protein phosphatase activities as judged by the counteractions of okadaic acid and Na3VO4 to the above effect. In addition, TCDD induced changes in nuclear protein kinase activities as well. Manganese-stimulated protein kinase was found to be the predominant type of nuclear protein phosphorylating activity affected by TCDD, with 60% of the total activity due to heparin-sensitive casein kinase II (CK II), a major nuclear protein kinase. The level of CK II activity in the nuclear protein preparation from adipose tissue of TCDD-treated guinea pigs (1 microgram/kg) in the presence of 100 nM heparin was only 35% of the control value after 24 hr. In addition, TCDD was found to increase the protein kinase C and microtubule-associated protein 2 kinase activities as early as 15 min after treatment in isolated adipose tissues in culture. Under in situ incubation conditions with explant tissues in culture, TCDD rapidly enhanced the DNA binding activity of the transcriptional factor AP-1, whereas the same treatment reduced c-Myc DNA binding activity. Genistein, a specific protein tyrosine kinase inhibitor, abolished the stimulatory effect of TCDD on AP-1 binding activity, but not on DNA binding activity of c-Myc. Phorbol ester (TPA) increased the binding activity of AP-1 and c-Myc, as expected. However, TCDD in combination with TPA caused a slight reduction in binding activity of both transcriptional factors. On the other hand, in the presence of forskolin, the stimulatory effect of TCDD on AP-1 binding activity and the inhibitory effect on c-Myc were still apparent. Okadaic acid almost abolished the binding activity of c-Myc, whereas in combination with TCDD a stimulatory effect was found. These observations are consistent with the idea that TCDD regulates the DNA binding activity of AP-1 and c-Myc mainly through modulating their states of phosphorylation by altering protein kinase and phosphatase activities.
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PMID:Regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) of the DNA binding activity of transcriptional factors via nuclear protein phosphorylation in guinea pig adipose tissue. 748 34

In this work, we demonstrate the signal-transducing mechanism of TGF-beta 1 for gene expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 (MCP-1) in clonal osteoblastic MC3T3-E1 cells. TGF-beta 1-induced JE/MCP-1 gene expression in the cells was inhibited markedly by H-7 (1-(5-isoguinolinesulfonyl)-2-O-methylpiperazine-dihydrochloride) and staurosporine, potent inhibitors of protein kinase. TGF-beta 1-induced expression of both early proto-oncogenes c-fos and c-jun in the cells was also inhibited by H-7 and staurosporine. Antisense oligonucleotides to c-fos and c-jun genes inhibited significantly the cytokine-induced JE/MCP-1 gene expression. Curcumin, a specific inhibitor of c-jun/AP-1, inhibited the cytokine-induced c-jun gene expression in a dose-dependent manner, though the c-fos gene expression was not affected. TGF-beta 1 stimulated transcriptionally the JE/MCP-1 gene expression, and this stimulation was inhibited significantly by curcumin. Curcumin-induced inhibition of the JE/MCP-1 gene product was also evidenced by both an assay involving immunoprecipitation with antiserum specific for JE/MCP-1 and an assay for monocyte chemotaxis. Curcumin markedly inhibited AP-1 binding activity to 12-tetradecanoyl phorbol-13-acetate-responsive element (TRE) in the cytokine-treated cells. Furthermore, H-7 and staurosporine also inhibited the binding activity to TRE in the cells treated by the cytokine. These results demonstrate that TGF-beta 1 induces expression of monocyte chemoattractant JE/MCP-1 via the transcriptional factor AP-1 induced by protein kinase in the osteoblastic cells.
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PMID:TGF-beta induces expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 via transcriptional factor AP-1 induced by protein kinase in osteoblastic cells. 760 15

T cell activation is triggered by antigen stimulation and is characterized by the production of a wide range of cytokines and other immunomodulators crucial for the growth and development of other haemopoietic cells. Activation also induces the T cells to express, on their cell surface, receptors that enable the T cell to respond to the various cytokines generated during an immune response. One well characterized event that occurs when mature T cells are activated is the production of the cytokine IL2 and the acquisition by the T cell of IL2 receptors. Interaction between IL2 and its cellular receptor then directs T cell growth. Expression of the IL2 gene in T cells is regulated by signalling pathways that originate from the T cell antigen receptor complex (TCR). This review discusses the role of p21ras in these events. The TCR regulates the activity of p21ras, and a range of experiments have shown that p21ras couples the TCR to an intracellular kinase cascade involving the serine/threonine kinase Raf-1 and the MAP kinase ERK2. Analysis of more distal receptor signals shows that p21ras controls a signalling pathway that cooperates with a calcium/calcineurin controlled signalling system to stimulate the transcriptional factor NFAT and hence the IL2 gene. These studies identify p21ras as a critical signalling molecule in immune cells.
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PMID:Regulation and function of p21ras in T lymphocytes. 772 60

Saccharomyces cerevisiae FUS3/DAC2 protein kinase, a homolog of mammalian mitogen-activated protein (MAP) kinase, inactivates a G1 cyclin encoded by the CLN3 gene to arrest cell division in the G1 phase and activates a transcriptional factor STE12 in response to mating pheromone during sexual conjugation. To elucidate the role of the FUS3/DAC2 gene product in the mating process, I constructed and characterized dac2 cln3 double mutants. Here, I show that FUS3/DAC2 is required for completion of cell fusion even in the dac2 cln3 double mutants in which the pheromone response is restored, suggesting that FUS3/DAC2 plays a positive role in cell fusion during conjugation. In addition, the cdc dac2 and cdc37 ste double mutants were constructed and investigated for their phenotypes to clarify the relationship between FUS3/DAC2, STE7 or STE11 and CDC gene products (CDC28, 36, 37 and 39). The results indicate that FUS3/DAC2 may act upstream of CDC28 and provide evidence that the G1 arrest and morphological changes conferred by the cdc37 mutation may require FUS3/DAC2 (MAP kinase), STE7(MEK) and STE11 (MEK kinase).
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PMID:Yeast homolog of mammalian mitogen-activated protein kinase, FUS3/DAC2 kinase, is required both for cell fusion and for G1 arrest of the cell cycle and morphological changes by the cdc37 mutation. 784 75

A novel cellular gene, SFA-2, was isolated by differential hybridization of a cDNA library, using probes obtained from an adult T-cell leukemia cell line in comparison with normal CD4+ T cells and MOLT-4 cell line. The mRNA of the SFA-2 gene is approximately 0.9-kb in size and encodes a protein of 125 amino acids, containing a basic region-leucine zipper DNA-binding domain. The N-terminal region of SFA-2 is rich in serine and contains a consensus sequence for casein kinase II phosphorylation. The SFA-2 gene was strongly expressed in mature T and B lymphocytes, and was up-regulated after transformation by human T-cell leukemia virus type I. The SFA-2 did not homodimerize efficiently but formed heterodimer preferentially with c-Jun. The SFA-2/c-Jun heterodimer bound preferentially to the AP-1 and CRE sites.
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PMID:SFA-2, a novel bZIP transcription factor induced by human T-cell leukemia virus type I, is highly expressed in mature lymphocytes. 863 63

The identification of cellular factors that are required to complete various steps of the HIV-1 life cycle may lead to the development of new therapeutics. One key step, transcription from the integrated provirus, is inhibited by members of two distinct classes of compounds, the flavonoids and the benzothiophenes, via an unknown mechanism, possibly involving a cellular factor. A marked specificity toward inhibiting HIV-1 transcription is evidenced by the ability of drug-treated cells to retain their proliferative and differentiation capabilities. In addition, the compounds do not impede the activation and function of the transcriptional factor NF-kappaB. Here we report on the identification of several cellular proteins that mediate the HIV-1 transcriptional inhibitory property of the flavonoid chrysin. Chemical and immunologic analyses identified these cellular proteins as the individual subunits of casein kinase II (CKII). Though structurally unrelated to chrysin, an HIV-1 inhibitory benzothiophene also bound selectively to CKII. Both chrysin and the benzothiophenes inhibited human recombinant CKII enzymatic activity and showed competitive kinetics with respect to ATP, analogous to the classic CKII inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). Moreover, DRB potently inhibited HIV-1 expression in chronically infected cells. CKII may regulate HIV-1 transcription by phosphorylating cellular proteins involved in HIV-1 transactivation that contain multiple CKII phosphorylation consensus sequences.
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PMID:Casein kinase II is a selective target of HIV-1 transcriptional inhibitors. 917 78

Cubitus interruptus (Ci) is a transcriptional factor that is positively regulated by the hedgehog (hh) signaling pathway. Recent work has shown that a 75-kDa proteolytic product of the full-length CI protein translocates to the nucleus and represses the transcription of CI target genes. In cells that receive the hh signal, the proteolysis of CI is inhibited and the full-length protein can activate the hh target genes. Because protein kinase A (PKA) inhibits the expression of the hh target genes in developing embryos and discs and the loss of PKA activity results in elevated levels of full-length CI protein, PKA might be involved directly in the regulation of CI proteolysis. Here we demonstrate that the PKA pathway antagonizes the hh pathway by phosphorylating CI. We show that the PKA-mediated phosphorylation of CI promotes its proteolysis from the full-length active form to the 75-kDa repressor form. The PKA catalytic subunit increases the proteolytic processing of CI and the PKA inhibitor, PKI, blocks the processing. In addition, cells do not process the CI protein to the 75-kDa repressor when all of the PKA sites in CI are mutated. Mutant CI proteins that cannot be phosphorylated by PKA have increased transcriptional activity compared with wild-type CI. In addition, exogenous PKA can increase further the transcriptional activity of the CI mutant, suggesting that PKA has a second positive, indirect effect on CI activity. In summary, we show that the modulation of the hh signaling pathway by PKA occurs directly at the level of CI phosphorylation.
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PMID:Protein kinase A directly regulates the activity and proteolysis of cubitus interruptus. 948 88

This laboratory reported previously that overexpressed heat shock protein 70 kDa (HSP-70) inhibited the activation of its transcriptional factor, HSF1. We had conducted experiments to understand the mechanisms whereby HSP-70 down-regulated the activation of HSF1. Genetically overexpressed HSP-70 had no effects on the HSF1 level in cytosol, but significantly inhibited phosphorylation of HSF1 in the nucleus. Transfection of cells with HSF1 cDNA resulted in increases in the unphosphorylated, but not phosphorylated, HSF1 levels in both the cytosol and nucleus. Because serine phosphorylation of various proteins was reduced in HSP-70 cDNA-transfected cells, we measured the activity of enzymes involved in serine phosphorylation. Overexpressed HSP-70 significantly inhibited the enzymatic activities of protein kinase A (PKA by 73 and 62% in the cytosol and membrane-bound fraction, respectively) and protein kinase C (PKC by 61% in membrane-bound fraction), whereas it activated that of protein phosphatase (PP by 33 and 86% in the cytosol and the membrane-bound fraction, respectively). Forskolin (a PKA stimulator), PMA (a PKC stimulator), and okadaic acid (an inhibitor of PP) were used to investigate whether HSP-70-induced changes in PKA, PKC, and PP were responsible for the HSF1 dephosphorylation. Forskolin did not change nuclear HSF1 phosphorylation, suggesting that decreases in PKA activity in HSP-70 overexpressing cells is not associated with HSF1 phosphorylation. PMA and okadaic acid induced an increase in HSF1 phosphorylation in both vector- and HSP-70 cDNA-transfected cells, although levels of phosphorylated HSF1 in HSP-70 cDNA-transfected cells were lower than those in vector-transfected cells. The PMA-induced increase in HSF1 phosphorylation in HSP-70 cDNA-transfected cells was blocked by pretreatment with staurosporine, a PKC inhibitor. These results suggest that overexpression of HSP-70 inhibits phosphorylation of HSF1 at serine residues by activating PP and inhibiting PKC activity.
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PMID:Overexpression of HSP-70 inhibits the phosphorylation of HSF1 by activating protein phosphatase and inhibiting protein kinase C activity. 953 17


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