Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of either muscarinic cholinergic or thrombin receptors increases phosphoinositide turnover, Ca2+ mobilization, and redistribution of protein kinase C and induces rapid transient increases in c-fos mRNA and c-jun mRNA in 1321N1 cells. To determine whether the increases in c-fos and c-jun mRNA induced by carbachol and thrombin are sufficient to stimulate AP-1-mediated transactivation, 1321N1 cells were transfected with a reporter carrying two copies of the tetradecanoyl phorbol acetate response element and the firefly luciferase gene. Thrombin was significantly more effective than carbachol at stimulating AP-1-mediated transactivation. To identify the factors underlying the difference in AP-1 activity induced by carbachol and thrombin, members of the fos and jun families which encode components of AP-1 were examined. Carbachol and thrombin have similar effects on expression of c-fos, fosB, fra-2, junB, and junD, both acutely and over a 24-h time course. However, whereas carbachol leads only to transient induction of c-jun (maximal at 0.5 h), thrombin induces a biphasic increase in c-jun mRNA--an initial peak at 0.5 h and a second, more-prolonged increase at 12 h. Thrombin but not carbachol also induces a late increase in fra-1 mRNA, which peaks at 12 h. The secondary increase in c-jun mRNA is associated with marked increases in c-Jun protein levels and AP-1 DNA-binding activity. The late induction of c-jun and fra-1 mRNA can be prevented by adding the antagonist hirudin 30 min after thrombin, which results in loss of thrombin-stimulated increases in c-Jun protein, AP-1 DNA-binding activity, and AP-1-mediated transactivation. These findings suggest that rapid and transient conduction of c-fos and c-jun mRNA is insufficient to induce prominent changes in gene transcription, while the sustained increase in c-jun mRNA and perhaps the late induction of fra-1 mRNA are required for generation of AP-1 DNA-binding activity and transactivation through AP-1.
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PMID:Biphasic increase in c-jun mRNA is required for induction of AP-1-mediated gene transcription: differential effects of muscarinic and thrombin receptor activation. 132 61

Calpain, an inactive proenzyme, translocates from the cytosol to the membrane upon binding calcium, and is activated at the membrane in the presence of calcium and PIP2. Activated calpain is very unstable and presumably used only once. Thus the primary targets of calpain are considered to be membrane or membrane-associated proteins. Activation of protein kinase C (PKC) occurs concomitantly with calpain at the membrane. Calpain hydrolyzes only the active PKC species leading to downregulation. Calpain participates in the transcriptional regulation by controlling the levels of transcription factors, c-Jun and c-Fos. The calpain gene is a TPA-responsive gene and its expression is stimulated by activation of PKC. Modulation of cellular signal transduction by controlling the levels of the component proteins, such as PKC, c-Jun and c-Fos is one of the important physiological roles of calpain.
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PMID:Modulation of cellular signals by calpain. 133 90

Transcription factor AP-1 is constituted by the various products of the fos and jun proto-oncogene family members, which associate as dimers to bind with variable efficiency to 12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive promoter elements (TREs). We have recently shown that DNA binding of AP-1 is regulated by an inhibitory protein, IP-1, whose activity is modulated by phosphorylation. Here it is shown that although AP-1 has a very high affinity for its recognition sequence, its binding to the TRE can be quickly inhibited by the addition of IP-1. IP-1 is more active on AP-1 complexes formed during a shorter period of time. IP-1 activity is blocked by stimulation of the protein kinase C (PKC) signal transduction pathway, achieved by treating HeLa cells with phorbol esters or with a diacylglycerol analog. We observed an increase in AP-1-DNA binding after treatment of the cells with either the calcium ionophore A-23187 or dibutyryl cAMP; this could be ascribed to inhibition of IP-1 activity. A decreased IP-1 activity also correlates with the increase in AP-1-DNA binding after stimulating cells with serum. This suggests that IP-1 is an important target of the various signal transduction pathways. No effect on AP-1 and IP-1 was detected in cells transformed by Ki-ras or v-raf; nor could an effect of inhibition of protein synthesis be observed. We also analysed IP-1 regulation upon differentiation of P19 embryonal carcinoma cells by retinoic acid. We conclude that IP-1 regulation has a pivotal role in the final modulation of Fos-Jun by signal transduction pathways.
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PMID:AP-1 (Fos-Jun) regulation by IP-1: effect of signal transduction pathways and cell growth. 143 49

We have analysed the effect of mitogenic lectins on c-Fos and c-Jun protein levels as well as on activator protein-1 (AP-1) binding and enhancer activity in Jurkat T-cells. Both c-Fos and c-Jun protein levels were increased after Con A and PHA stimulation. Since T-cell stimulation increases both intracellular Ca2+ and cAMP levels and activates protein kinase C (PKC), the possible involvement of these intracellular messengers in c-Fos and c-Jun induction was tested. PMA, which directly activates PKC, mimicked the effect of the lectins on c-Fos and c-Jun, but elevation of either intracellular Ca2+ or cAMP levels had little or no effect. The mitogen-induced increase of c-Fos and c-Jun immunoreactivity was inhibited by H-7, a kinase inhibitor with relatively high specificity for PKC, and less efficiently by H-8, a structurally related kinase inhibitor less active on PKC, but more active on cyclic nucleotide-dependent kinases. Con A stimulation was found to increase both binding of AP-1 to the AP-1 consensus sequence, TRE, and AP-1 enhancer activity, in Jurkat cells. PMA was also found to increase the AP-1 enhancer activity, whereas elevation of Ca2+ or cAMP had only minor effects. We conclude that stimulation with mitogenic lectins is sufficient to increase both c-Fos and c-Jun protein levels, AP-1 binding and AP-1 enhancer activity in Jurkat cells and that they act via mechanisms that could involve the activation of PKC.
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PMID:Mitogen stimulation of T-cells increases c-Fos and c-Jun protein levels, AP-1 binding and AP-1 transcriptional activity. 151 Aug 78

The TPA-inducible transcription factor AP-1, consisting of homo- or hetero-dimers of members of the Jun- and Fos-families, regulates transcription of a wide variety of genes containing the TPA response element (TRE). In P19 embryonal carcinoma (EC) cells, Jun D is the only component of AP-1 expressed, while in these cells until now none of the members of the jun- and fos-families have been found to be inducable by external stimuli. Here we demonstrate that Jun B is the only member of the Jun- and Fos-families that is induced by Epidermal Growth Factor (EGF) in transfected murine P19 EC cells, expressing functional human EGF receptors (hEGF-Rs). Induction of jun B can be mimicked in wild type P19 EC cells by the synergistic action of the phorbol ester TPA and the calcium ionophore A23187, through activation of signal transduction pathways, that are activated simultaneously by EGF. The EGF induced jun B expression in the hEGF-R expressing P19 EC cells is mediated by an inverted repeat (IR) sequence in the jun B promoter, previously shown to be responsive to both PKC and PKA signal transduction. Transactivation of the IR sequence by EGF can be blocked completely by prior expression of antisense Jun D, but not by antisense c-Jun. These studies therefore implicate Jun D in the regulation of immediate early gene expression by external stimuli.
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PMID:EGF-induced jun B-expression in transfected P19 embryonal carcinoma cells expressing EGF-receptors is dependent on Jun D. 173 90

c-Jun protein, and AP1/PEA1 transcription factor component, is a typical short-lived protein, and like other short-lived proteins such as c-Fos, contains PEST regions. Calcium-dependent neutral protease (calpain), a candidate for the degradation of PEST-containing proteins, digests c-Jun and c-Fos efficiently in vitro. This is the first demonstration that transcription factors are substrates for calpain. The C-terminal portion of c-Jun is relatively resistant to calpain such that an 18kDa fragment, which includes the DNA binding domain, accumulates under moderate digestion conditions. The activity of c-Jun in cultured cells can be modified by changing the level of calpastatin, an endogenous calpain inhibitor, indicating that c-Jun is also a substrate for calpain in vivo.
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PMID:Degradation of transcription factors, c-Jun and c-Fos, by calpain. 190 91

The nuclear oncoproteins fos and jun are associated as a heterodimer which binds to TPA (PMA or TPA: phorbol 12-myristate 13-acetate)- responsive promoter elements (TRE), the recognition site for the transcription factor AP-1. The fos/jun heterodimer has a higher affinity to the TRE and stimulates transcription of responsive genes more than the jun homodimer. The association of these two oncoproteins may play a central role in signal transduction and regulation of cell proliferation and differentiation. We further defined the regulation of fos and jun by studying their inducibility by second messengers in cells of hematopoietic origin. In THP-1 monocytic leukemia cells fos and jun mRNA levels are regulated in a coupled manner by second messengers activated after membrane phospholipid turnover. Addition of phospholipase C to cells, as well as stimulation of protein kinase C and release of intracellular Ca2+, caused a rapid induction of fos and jun mRNA levels, but the induction of jun mRNA showed a more persistant and less transient pattern than fos. In contrast to the phosphoinositol system, stimulation of the adenylate cyclase pathway in THP-1 cells induced only fos transcription whereas jun mRNA levels remained unchanged. A similar uncoupling of fos and jun inducibility was found after phorbol ester addition to the human erythroleukemia cell line HEL and the human promyelocytic cell line HL-60. The uncoupling of fos and jun levels might predispose cells to the formation of combinatorial transcription complexes of a different composition and activity than the fos/jun heterodimer. Indeed, nuclear extracts from THP-1 cells before or after activation of the phosphinositol or adenylate cyclase second messenger pathways revealed a correlation in fos and jun expression and specific binding of the heterocomplex to a TRE sequence.
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PMID:Coupled and uncoupled induction of fos and jun transcription by different second messengers in cells of hematopoietic origin. 215 73

We have analyzed the modulation of amyloid beta-protein precursor (APP) gene expression in human umbilical vein endothelial cells (HUVEC). The level of the APP mRNA transcripts increased as HUVEC reached confluency. In confluent culture the half-life of the APP mRNA was 4 hr. Treatment of the cells with human-recombinant interleukin 1 (IL-1), phorbol 12-myristate 13-acetate, or heparin-binding growth factor 1 enhanced the expression of APP gene in these cells, but calcium ionophore A23187 and dexamethasone did not. The protein kinase C inhibitor 1-(isoquinolinsulfonyl)-2-methylpiperazine (H7) inhibited IL-1-mediated increase of the level of APP transcripts. To map IL-1-responsive elements of the APP promoter, truncated portions of the APP promoter were fused to the human growth hormone reporter gene. The recombinant plasmids were transfected into mouse neuroblastoma cells, and the cell medium was assayed for the human growth hormone. A 180-base-pair region of the APP promoter located between position -485 and -305 upstream from the transcription start site was necessary for IL-1-mediated induction of the reporter gene. This region contains the upstream transcription factor AP-1 binding site. These results suggest that IL-1 upregulates APP gene expression in HUVEC through a pathway mediated by protein kinase C, utilizing the upstream AP-1 binding site of the APP promoter.
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PMID:Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. 250 93

1. The bovine kappa-casein gene has been isolated as a series of overlapping lambda clones and shown to consist of five exons distributed over a total length of approximately 13 kb. Most of the mature protein-coding sequence is contained in a single large exon. 2. Approximately 65% of the gene has been sequenced together with portions of the 5'- and 3'-flanking sequences. The immediate 5'-flanking sequence contains several motifs which are characteristic of upstream regions including a TATA box, a CAAT box, a sequence similar to that recognized by transcription factor AP-1 and a purine-rich sequence resembling that found upstream in all other lactoprotein genes. Other possible regulatory sequences are found upstream of exon 4. 3. The organization of the kappa-casein gene, together with its upstream sequence, confirms previous conclusions that it is unrelated to the calcium-sensitive-casein gene family to which it is linked. Evidence is presented which supports a previous suggestion that kappa-casein and the fibrinogens are evolutionarily related. 4. Intron sequences contain several examples of the A family of the artiodactyl Alu-like repeated sequences, together with a single example of a C-family sequence. The remainders of the introns of the kappa-casein gene, compared with the repeat elements and exons, are A + T-rich. 5. Among the lambda clones isolated, representatives were found of the A and B genetic variants which can be distinguished by restriction-enzyme analysis. Several other examples of polymorphisms in the non-coding region were found.
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PMID:Isolation and characterization of the bovine kappa-casein gene. 320 64

We recently reported that gastrin and glycine-extended progastrin processing intermediates (G-Gly) exert growth-promoting effects on AR4-2J cells (derived from rat pancreas) via interaction with distinct receptors. In this study we sought to investigate the mechanisms by which gastrin and G-Gly stimulate cell proliferation. While gastrin increased [Ca2+]i in AR4-2J cells, G-Gly had no effect. Similarly, G-Gly had no effect either on basal and 10(-7) M vasoactive intestinal polypeptide-stimulated cAMP generation, although gastrin is known to inhibit cAMP generation. Gastrin dose dependently stimulated AR4-2J cell mRNA content of both c-fos and c-jun, two genes known to function in regulating cell proliferation, but G-Gly had no effect. Gastrin also induced the expression of luciferase in AR4-2J cells transfected with a construct consisting of a luciferase reporter gene coupled to the serum response element of the c-fos gene promoter. In similar fashion, gastrin stimulated the activity of mitogen-activated protein kinase, an enzyme known to mediate the induction of the c-fos serum response element in response to growth factor stimulation. Although G-Gly had none of these effects of gastrin in AR4-2J cells, it stimulated activity of c-Jun amino-terminal kinase, an enzyme known to phosphorylate and transcriptionally activate c-Jun. These data support the notion that gastrin stimulates cell proliferation by inducing c-fos and c-jun gene expression, while G-Gly acts by post-translationally regulating early gene transcriptional activation. Our studies represent a novel model in which both the precursor and the product of a key processing reaction, peptide alpha-amidation, act cooperatively to stimulate cell proliferation via distinct receptors linked to different signal transduction pathways.
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PMID:Gastrin and glycine-extended progastrin processing intermediates induce different programs of early gene activation. 749 34


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