Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We have utilized the human 4F2 heavy chain (4F2HC) gene as a model system in studies designed to elucidate the molecular events involved in regulating inducible gene expression during normal human T-cell activation. In previous studies we have shown that steady state levels of 4F2HC mRNA are induced 50-60-fold within 6 h of T-cell activation by phytohemagluttinin (PHA) and that the induction of 4F2HC gene expression involves both the protein kinase C and calcium-mediated activation pathways. Despite the fact that the 4F2HC gene is highly regulated in T cells, the 5' upstream region of the 4F2HC gene contains a housekeeping promoter which is G + C rich, lacks TATA or CCAAT sequences, and contains four potential binding sites for the ubiquitous Sp 1 transcription factor. The major regulatory elements of the 4F2HC gene do not reside within this 5' upstream region but instead, map to the exon 1-intron 1 region of the gene. The low levels of mature 4F2HC mRNA in resting T cells result from a block to transcription elongation within the exon 1-intron 1 region of the gene rather than promoter inactivity. Phorbol ester stimulation of resting T cells induces 4F2HC expression by removing this block to transcription elongation. We now report that in addition to its ability to serve as a transcriptional attenuator, the 4F2HC first intron contains a powerful enhancer element which is active in a wide variety of cell types including malignant human T cells. Full enhancer activity is displayed by a 186 bp fragment of the first intron which contains binding sites for two novel nuclear proteins (NF-4FA and NF-4FB) which flank a consensus binding site for the AP-1 transcription factor. A cDNA encoding the NF-4FB enhancer binding protein has been cloned by screening a lambda gt11 cDNA library with a rabiolabelled oligonucleotide corresponding to the NF-4FB recognition sequence.
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PMID:The 4F2 heavy chain gene: a molecular model of inducible gene expression in human T cells. 278 62

We have purified and characterized the 50 kd activator protein 2 (AP-2), another enhancer-binding protein interacting with the human metallothionein IIA (hMT-IIA) gene control region. Purified AP-2 activates transcription in vitro from a hybrid promoter containing hMT-IIA upstream sequences. AP-2 also recognizes control elements of the human growth hormone, c-myc, and H-2Kb genes, and the SV40 and bovine papilloma virus enhancers. Multiple synthetic copies of the hMT-IIA high-affinity AP-2 binding site can act as efficient, cell-type-specific enhancer elements; their activity increases after treatment of cells with phorbol ester or cAMP-elevating agents. In contrast, a synthetic enhancer recognized by factor AP-1 is activated only by phorbol ester. AP-2 appears to mediate transcriptional activation in response to two different signal-transduction pathways, one involving the phorbol-ester- and diacylglycerol-activated protein kinase C, the other involving cAMP-dependent protein kinase A.
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PMID:Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. 282 55

The enhancer-binding protein AP-1 has been purified to greater than 95% homogeneity from HeLa cells by sequence-specific DNA affinity chromatography and identified as a 47 kd polypeptide. Purified AP-1 activates transcription in vitro of the wild-type human metallothionein IIA (hMT IIA) gene but not mutant hMT IIA promoters lacking AP-1 recognition sites. DNAase I protection analysis indicates that genetically defined enhancer elements in hMT IIA, SV40, and the human collagenase gene contain high-affinity AP-1-binding sites, each with a conserved recognition motif, TGACTCA. These three genes are transcriptionally induced by treatment of cells with the tumor promoter TPA. Here we demonstrate that multiple synthetic copies of the consensus AP-1-binding site can act as TPA-inducible enhancers in various plasmid constructs after transfection into HeLa cells. These findings suggest that AP-1 is a transcription factor that functions by interacting with a specific enhancer element, and that its activities may be modulated by treatment of cells with TPA, known to stimulate protein kinase C.
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PMID:Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. 303 33

Binding of the human transcription factor Jun/AP-1 to a conserved 8 bp nucleotide sequence (TRE) is responsible for increased transcription of different cellular genes in response to tumor promoters, such as TPA, and serum factors. Enhanced Jun/AP-1 activity in TPA-stimulated cells is regulated by two different mechanisms: a posttranslational event acting on pre-existing Jun/AP-1 molecules, and transcriptional activation of jun gene expression leading to an increase in the total amount of Jun/AP-1. Induction of jun transcription in response to TPA is mediated by binding of Jun/AP-1 to a high-affinity AP-1 binding site in the jun promoter region. Site-specific mutagenesis of this binding site prevents TPA induction and trans-activation by Jun/AP-1. These results clearly demonstrate that jun transcription is directly stimulated by its own gene product. This positive regulatory loop is likely to be responsible for prolonging the transient signals generated by activation of protein kinase C.
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PMID:The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. 314 89

Human monoblastoid leukemia U937 cells differentiate to monocyte/macrophage upon treatment with phorbol ester, 12-o-tetradecanoylphorbol-13-acetate (TPA). Previous studies, including our own, have demonstrated that drug-induced differentiation of leukemia cells is associated with genetic and enzymatic activations of protein tyrosine phosphatases (PTPases). In this study, to further investigate a relationship between PTPase activation and leukemic differentiation, we established TPA-resistant U937 variant UT16 cells. Unlike known TPA-resistant cells whose resistance is mainly due to lack or down modulation of protein kinase C (PKC), UT16 cells showed TPA-induced activation of PKC, Raf-1, and ERK/MAP kinases similar to the parental U937 cells. Interestingly, however, UT16 cells exhibited altered binding activity of AP-1 complexes, decreased ability to induce c-jun and c-fos gene expressions, and failure to differentiate to a monocytic lineage. Based on these observations, UT16 cells could be considered a novel type of TPA-resistant cell. Among UT16 cells, most of TPA-inducible PTPase genes, PTP-1C, PTP-MEG2, P19-PTP, HPTP epsilon, and PTP-U1, did not respond to TPA. Consistently, TPA increased PTPase enzymatic activity in U937 but not in UT16 cells. Taken together, activation of PTPases is well correlated with TPA-induced differentiation of U937 cells. These findings indicate that gene expression and enzymatic activity of some PTPase isozymes described here are regulated by a TPA-mediated signaling event and are likely to be used as biomarkers for the monocytic differentiation of myeloid leukemia cells.
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PMID:Phorbol ester-resistant monoblastoid leukemia cells with a functional mitogen-activated protein kinase cascade but without responsive protein tyrosine phosphatases. 747 24

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

B16 melanoma cells differentiate upon treatment with retinoic acid (RA). This differentiation process is accompanied by an increase of protein kinase C alpha (PKC alpha) mRNA and protein levels. Overexpression of PKC alpha in these cells results in a more differentiated phenotype, suggesting the importance of this protein in the control of differentiation by RA. The purpose of the study reported here was to determine the subcellular distribution of the RA-induced PKC alpha, whether the RA-induced increase in PKC alpha protein levels was accompanied by an increase in in situ enzyme activity, and whether RA altered AP-1 transcriptional activity. We found that RA treatment increased PKC alpha protein levels in all subcellular compartments examined, but it also induced a selective enrichment in nuclear-associated PKC alpha levels. Treating cells with an active phorbol ester induced translocation of PKC alpha to membrane fractions, but had no effect on nuclear PKC alpha levels. RA also increased PKC enzymatic activity in intact cells as determined by phosphorylation of the PKC-specific endogenous substrate MARCKS. However, while RA induced a five- to eightfold increase in total cellular PKC alpha protein levels, it only increased MARCKS phosphorylation by twofold. In light of the increase in in situ PKC enzyme activity and the enrichment of nuclear PKC alpha, we determined whether AP-1 activity might be increased in RA-treated cells. Use of luciferase reporter gene constructs with or without AP-1 elements transfected into B16 cells indicated that RA induced a four- to fivefold increase in AP-1 transcriptional activity. These results suggest a hypothesis whereby RA-induced nuclear PKC alpha might lead to increased AP-1 activity and show that RA-induced growth inhibition and differentiation are not always accompanied by an inhibition of AP-1 activity as has been proposed by other investigators.
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PMID:Retinoic acid specifically increases nuclear PKC alpha and stimulates AP-1 transcriptional activity in B16 mouse melanoma cells. 749 37

Na+/H+ exchanger (NHE) activity is regulated by several types of receptors directly coupled to distinct classes (i.e. Gs, Gi, Gq, and G12) of heterotrimeric (alpha beta gamma) GTP-binding proteins (G proteins), which, upon activation, modulate production of various second messengers (e.g. cAMP, cGMP, diacylglycerol, inositol trisphosphate, and Ca2+). Recently, four isoforms of the rat Na+/H+ exchanger were identified by molecular cloning. To examine their intrinsic responsiveness to G protein and second messenger stimulation, three of these isoforms, NHE-1, -2, and -3, were stably expressed in mutant Chinese hamster ovary cells devoid of endogenous NHE activity (AP-1 cells). Incubation of cells with either AIF4-, a general agonist of G proteins, or cholera toxin, a selective activator of G alpha s that stimulates adenylate cyclase, accelerated the rates of amiloride-inhibitable 22Na+ influx mediated by NHE-1 and -2, whereas they inhibited that by NHE-3. Similarly, short term treatment with phorbol 12-myristate 13-acetate, which mimics diacylglycerol activation of protein kinase C (PKC), or with agents (i.e. forskolin, 8-(4-chlorophenylthio)-cAMP, and isobutylmethylxanthine) that lead to activation of cAMP-dependent protein kinase (PKA) also stimulated transport by NHE-1 and NHE-2 but depressed that by NHE-3. The effects of phorbol 12-myristate 13-acetate were blocked by depleting cells of PKC or by inhibiting PKC using chelerythrine chloride, confirming a role for PKC in modulating NHE isoform activities. Likewise, the PKA antagonist, H-89, attenuated the effects of elevated cAMPi on NHE-1, -2, and -3, further demonstrating the regulation by PKA. Unlike cAMPi, elevation of cGMPi by treatment with dibutyryl-cGMP or 8-bromo-cGMP had no influence on NHE isoform activities, thereby excluding the possibility of a role for cGMP-dependent protein kinase in these cells. These data support the concept that the NHE isoforms are differentially responsive to agonists of the PKA and PKC pathways.
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PMID:Plasma membrane Na+/H+ exchanger isoforms (NHE-1, -2, and -3) are differentially responsive to second messenger agonists of the protein kinase A and C pathways. 749 49

We studied the effects of RRR-alpha-tocopherol and RRR-beta-tocopherol in smooth muscle cells from rat (line A7r5) and human aortas. RRR-alpha-Tocopherol, but not RRR-beta-tocopherol, inhibited smooth muscle cell proliferation in a dose-dependent manner at concentrations in the range from 10 to 50 mumol/L. RRR-beta-Tocopherol added simultaneously with RRR-alpha-tocopherol prevented growth inhibition. The earliest event brought about by RRR-alpha-tocopherol in the signal transduction cascade controlling receptor-mediated cell growth was the activation of the transcription factor AP-1. RRR-beta-tocopherol alone was without effect but in combination with RRR-alpha-tocopherol prevented the AP-1 activating effect of the latter. Protein kinase C was inhibited by RRR-alpha-tocopherol and not by RRR-beta-tocopherol, which also in this case prevented the effect of RRR-alpha-tocopherol. Calyculin A, a protein phosphatase inhibitor, prevented the effect of RRR-alpha-tocopherol on protein kinase C. The data can be rationalized by a model in which a tocopherol-binding protein discriminates between RRR-alpha-tocopherol and RRR-beta-tocopherol and initiates a cascade of events at the level of cell signal transduction that leads to the inhibition of cell proliferation.
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PMID:Vitamin E: a sensor and an information transducer of the cell oxidation state. 749 29


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