Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the mammalian renal proximal tubule, protein kinase A (PKA) plays an important role in mediating hormonal regulation of apical membrane Na/H exchanger activity. This exchanger is likely encoded by NHE-3. The present studies examined regulation of NHE-3 by PKA. NHE-3 was stably expressed in Na/H exchanger-deficient fibroblasts (AP-1/NHE-3 cells). PKA activation (0.1 mM 8-BrcAMP x 20 min) inhibited NHE-3 activity by 39% (P < 0.01) with no change in NHE-3 protein abundance in the plasma membrane. To define the structural requirements for PKA-mediated inhibition, full-length NHE-3 and a cytoplasmic domain-truncated mutant (NHE-3 delta cyto) were expressed in Xenopus laevis oocytes. 8-BrcAMP inhibited NHE-3 activity by 27% (P < 0.05), an effect that was blocked by 10(-7) M PKA inhibitor peptide. NHE-3 delta cyto had baseline activity similar to that of full-length NHE-3 but its activity was not regulated by 8-BrcAMP. The purified recombinant cytoplasmic domain of NHE-3 was phosphorylated in vitro by the catalytic subunit of PKA on serine residues. In AP-1/NHE-3 cells, NHE-3 was immunoprecipitated as a approximately 87-kD phosphoprotein. Addition of 0.1 mM 8-BrcAMP increased the phosphocontent of NHE-3 by threefold. In summary, acute activation of PKA inhibits NHE-3 activity, an effect that is likely mediated by phosphorylation of its cytoplasmic domain.
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PMID:Activation of protein kinase A acutely inhibits and phosphorylates Na/H exchanger NHE-3. 759 4

The mechanisms by which pX, the transactivator of the hepatitis B virus (HBV), exerts its effects on transcription of viral and cellular genes and affects cell-growth regulation have not yet been fully defined. Previous reports suggested the possibility of a direct interaction of pX, which lacks intrinsic DNA-binding activity, with components of the cellular transcription machinery. More recent investigations support the hypothesis that pX might activate cellular kinases involved in transcriptional regulation and growth control. We characterized the mechanisms of AP-1 transcription factor activation by pX and, in particular, the role of cellular proteins involved in the intracellular signal transduction of growth-factor receptors. The observation that the overexpression of c-fos and c-jun in the cells results in a clear augmentation of the effects of pX on TRE-directed transcription and the induction of the DNA-binding activity of c-jun/c-fos heterodimers by AP1-depleted nuclear extracts from pX-expressing cells strongly supports the involvement of post-translational modifications. In both HeLa and undifferentiated F9 cells, pX was able to increase the activity of exogenous transfected c-jun but not of c-jun mutants bearing mutations in the serine residues located in the amino-terminal transcriptional activation domain. Moreover, by use of Ha-ras and Raf-1 dominant negative mutants, we show that both Ha-ras and Raf-1 are required for pX-induced activation of c-jun transcriptional activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of intracellular signal transduction pathways by the hepatitis B virus transactivator pX. 760 67

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

Basic fibroblast growth factor (bFGF) has been shown to be a potent mitogen and a promoter of angiogenesis. It has been hypothesized that the expression of the bFGF gene may be induced by stress of various types. To test that hypothesis, we investigated the expression of the bFGF gene during heat treatment in adriamycin-resistant (MCF-7/ADR) and -sensitive (MCF-7) human breast carcinoma cells. Under normal growth conditions, the bFGF mRNA was detected in MCF-7/ADR cells, while it was not detectable in MCF-7 cells by Northern blot analysis. During heating at 41 degrees C, the level of bFGF mRNA increased in MCF-7/ADR cells and the message became detectable in the MCF-7 cell line. However, after continuous heating at 41 degrees C for 24 h, the bFGF mRNA level decreased to control level in MCF-7/ADR cells. Interestingly, simultaneous treatment with heat and 60 micrograms/ml H-7 (1-(isoquinolinylsulfonyl)-2-methylpiperazine, a potent PKC inhibitor) decreased the level of bFGF mRNA in MCF-7/ADR cells. These results suggest that a protein kinase, likely PKC, is involved in the transcriptional regulation of the heat-enhanced bFGF gene expression in human breast carcinoma cells. Although no heat shock element can be identified in the promoter of the bFGF gene, we observed that the AP-1 binding activity to a TPA responsive element (TRE)-like sequence in the promoter of bFGF gene was enhanced by heat, as tested by mobility shift assay. Antibody developed against the c-Jun and c-Fos proteins inhibited the AP-1 binding activity to TRE. Therefore, the AP-1 complex appears to be responsible for the heat-enhanced binding to the TRE-like motif of the bFGF gene. Furthermore, the increased AP-1 binding activity does not require new protein synthesis but activation of the preexisting c-Jun proteins.
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PMID:Heat-induced bFGF gene expression in the absence of heat shock element correlates with enhanced AP-1 binding activity. 762 86

Androgen (R1881) induced transcriptional activity of the human androgen receptor, stably expressed in CHO cells, can be stimulated an extra 2-fold by the addition of the protein kinase C activator, 4 beta-phorbol 12-myristate 13-acetate (PMA). This extra stimulation is not observed when the protein kinase A activator bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP) is used. The transcriptional activity was measured using a reporter plasmid containing the MMTV-promoter, coupled to the luciferase gene. The effect of PMA on R1881-induced transcription was not due to a higher expression level of the androgen receptor. Also, no extra phosphorylation of the androgen receptor could be measured after incubation with PMA. When GRE-tk-LUC and PSA-LUC reporters were used, the synergistic effect of PMA could not be observed. The findings on the composite MMTV-LTR promoter can be explained by either a direct synergistic interaction between occupied AP-1 like responsive elements and the androgen receptor or via an unknown transcription factor activated by the PKC pathway and interacting with the androgen receptor.
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PMID:Synergism between androgens and protein kinase-C on androgen-regulated gene expression. 767 38

The N-formyl peptide chemoattractant receptor (fMLF-R) is a cell-surface, G-protein-coupled glycoprotein that mediates the directed locomotion of neutrophils upon binding N-formylated peptides. The fMLF-R is encoded primarily by a 1.6-kb mRNA in differentiated HL-60 and U937 cells, although larger less abundant transcripts are present. To study the origin of different fMLF-R transcripts, the genetic linkage of chemotactic receptor genes, and the regulation of fMLF-R gene expression, we determined the copy number, chromosomal location, structural organization, and 5'-flanking sequence of the human fMLF-R gene. BamHI restriction fragments derived from a human fMLF-R genomic cosmid clone were isolated, subcloned, and sequenced. These data indicate that the fMLF-R structural gene is approximately 7.5 kb in length and is comprised of two exons separated by an approximately 5.0-kb intron. The first exon encodes 66 bp of the 5'-untranslated sequence, while exon 2 encodes the coding and 3'-untranslated sequences. The genomic organization of the fMLF-R gene is similar to that of the adrenergic beta-1 and beta-2 G-protein-coupled receptor genes in that the coding sequence is contained in a single exon. The different 3'-untranslated sequences observed in fMLF-R cDNA clones are contiguous in the genomic structure, thereby indicating that these clones are derived in part by alternative polyadenylation. Southern blot analysis using human X hamster somatic cell hybrids and in situ hybridization indicated that the h-fMLF-R gene is located on chromosome 19q13.3. Primer extension experiments using dbcAMP-differentiated U937 RNA indicated a single transcriptional initiation site. Sequence analysis 5' of the transcriptional initiation site indicated possible cis-acting motifs that may regulate fMLF-R gene expression. These included AP-1 and CK-2 consensus sequences that bind nuclear factors of the Fos/Jun family and NF-GMb, respectively.
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PMID:Structure, 5'-flanking sequence, and chromosome location of the human N-formyl peptide receptor gene. A single-copy gene comprised of two exons on chromosome 19q.13.3 that yields two distinct transcripts by alternative polyadenylation. 768 42

Fusarium moniliforme (FM) is a major fungal pathogen of corn and is involved with stalk rot disease. FM is widely spread throughout the world, including the United States. Most strains of FM produce several mycotoxins, the most prominent of which is called fumonisin. Recent epidemiological studies indicated that ingestion of fumonisin correlates with a higher incidence of esophageal cancer in Southern and Northern Africa and China. Furthermore, fumonisin causes a neurodegenerative disease in horses, induces hepatic cancer in rats, and induces pulmonary edema in swine. Considering that high levels of fumonisin have been detected in healthy and diseased corn grown in the United States, fumonisin may pose a health threat to humans and livestock animals. Structurally, fumonisin resembles sphingolipids which are present in the membranes of animal and plant cells. At the present time, very little is known concerning the mechanism by which fumonisin elicits its carcinogenic effect. Our studies indicate that fumonisin represses expression of protein kinase C and AP-1-dependent transcription. In contrast, fumonisin stimulated a simple promoter containing a single cyclic AMP response element. Since fumonisin did not alter protein kinase A activity, it appears that cyclic AMP response element activation was independent of protein kinase A. It is hypothesized that the ability of fumonisin to alter signal transduction pathways plays a role in carcinogenesis.
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PMID:Repression of protein kinase C and stimulation of cyclic AMP response elements by fumonisin, a fungal encoded toxin which is a carcinogen. 771 70

Aspirin-like drugs (ALD) induce calcium mobilization, an essential component of T cell activation, but do not induce the biosynthesis of IL-2. To understand the extent to which ALD may mimic mitogenic stimulation, we studied cytoplasmic and nuclear signaling steps in ALD-treated T cells. We found that ALD induce a transient activation of protein kinase (PKC) but have no effect (in comparison to anti-CD3 antibodies) on protein tyrosine phosphorylation nor on PCL gamma 1 tyrosine phosphorylation. ALD-induced calcium mobilization and PKC activation are independent of tyrosine protein kinase activity as shown by the lack of effect of herbimycin, a tyrosine-protein kinase-specific inhibitor. Although we detected no IL-2 mRNA in ALD-treated cells, the nuclei of these cells contain proteins capable of binding to three regulatory sequences in the IL-2 promoter region: NFAT, NF kappa B, and AP-1. These binding activities are expressed only in activated T cells. The expression of AP-1 depended on calcium mobilization and PKC activation. These data suggest that ALD cause transient but significant changes in T cell transmembrane signaling, although some events induced by stimulation with anti-CD3 antibodies are not induced by ALD. The signal is transmitted to the nucleus and induces DNA-binding activity by several transcription factors. However, the ALD stimulus is not capable of causing complete T cell activation.
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PMID:Induction of transcription factors in human T lymphocytes by aspirin-like drugs. 772 85

The major regulators of the c-jun promoter are ATF-2 and c-Jun. They act as pre-bound heterodimers on two 'AP-1-like' sites, and are preferentially addressed by different types of extracellular signals. The transactivating potential of ATF-2 is stimulated to a higher extent than that of c-Jun by a broad group of agents causing DNA damage and other types of cellular stress, such as short-wavelength UV, or the alkylating compounds N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) or methylmethanesulphonate (MMS). In contrast, treatment with the phorbol ester TPA preferentially enhances c-Jun-dependent transactivation but does not affect ATF-2. Accordingly, UV and MMS but not TPA induce c-jun transcription in F9 cells, which express ATF-2, but not c-Jun. Stimulation of ATF-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the N-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (SAPKs) which bind to, and phosphorylate ATF-2 in vitro. However, p46 and p54 kinase activity is not increased by phorbol ester, which strongly suggests that the protein kinase phosphorylating c-Jun in response to TPA is distinct from SAPKs and does not act on ATF-2. Our data demonstrate that distinct signal transduction pathways converge at c-Jun/ATF-2, whereby each subunit is individually addressed by a specific class of protein kinases. This allows fine tuned modulation of c-jun expression by a large spectrum of extracellular signals.
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PMID:ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. 773 30

We examined the common signal transduction mechanisms governing collagenase (MMP-1), stromelysin-1 (MMP-3), and tissue inhibitor of metalloproteases (TIMP-1) gene expression in human synovial fibroblasts for insight into the pathophysiology of arthritis. MMP-1, MMP-3, and TIMP-1 expression and synthesis were induced in cultured human synoviocytes with recombinant human interleukin 1 beta in the absence or presence of either chemical inhibitors of protein kinase A and C (PKA, PKC), or prostaglandin E2, or cyclic AMP (cAMP) mimetics. We used enzyme immunoassays (EIA) to determine MMP-1, MMP-3, and TIMP-1 antigen levels in spent culture medium and Northern hybridization to measure steady state mRNA expression levels. Extracellular signals (e.g., IL-1, phorbol myristic acetate) that result in the activation of cytoplasmic PKC augment in tandem the expression and synthesis of MMP-1, MMP-3, and TIMP-1 in human synovial fibroblasts. In addition, such signals induce nuclear transcription factors (e.g., activator protein 1) that bind to common gene regulatory elements and augment promoter activity of MMP-1, MMP-3, and TIMP-1 gene promoter constructs. In contrast, signals that activate PKA oppose PKC mediated signals, in that the expression of MMP-1, MMP-3, and TIMP-1 are suppressed. Experimental data suggest that the expression of MMP-1, MMP-3, and TIMP-1 are coordinated through a series of common cytoplasmic signal transducing pathways, cis regulatory elements, and nuclear trans acting factors.
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PMID:Coordinate regulation of matrix metalloproteases and tissue inhibitor of metalloproteinase expression in human synovial fibroblasts. 775 15


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