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)

The involvement of serine/threonine protein phosphatases in signaling pathways which modulate the activity of the transcription factor AP-1 was examined. Purified protein phosphatase types 1 (PP1) and 2A (PP2A) were microinjected into cell lines containing stably transfected lacZ marker genes under the control of an enhancer recognized by AP-1. Microinjection of PP2A potentiated serum-stimulated beta-galactosidase expression from the AP-1-regulated promoter. Similarly, transient expression of the PP2A catalytic subunit with c-Jun resulted in a synergistic transactivation of an AP-1-regulated reporter gene. PP2A, but not PP1, potentiated serum-induced c-Jun expression, which has been previously shown to be autoregulated by AP-1 itself. Consistent with these results, PP2A dephosphorylated c-Jun on negative regulatory sites in vitro, suggesting one possible direct mechanism for the effects of PP2A on AP-1 activity. Microinjection of PP2A had no effect on cyclic AMP (cAMP)-induced expression of a reporter gene containing a cAMP-regulated promoter, while PP1 injection abolished cAMP-induced gene expression. Taken together, these results suggest a specific role for PP2A in signal transduction pathways that regulate AP-1 activity and c-Jun expression.
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PMID:Protein phosphatase 2A potentiates activity of promoters containing AP-1-binding elements. 838 5

Previous studies have demonstrated that human HL-60 myeloid leukemia cells differentiate in response to phorbol esters. This event is associated with induction of the c-jun early response gene and appearance of a monocytic phenotype. The present studies have examined the effects of vincristine-selected, multidrug resistance on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced HL-60 cell differentiation. The results demonstrate that multidrug-resistant HL-60 cells, designated HL-60/vinc, fail to respond to TPA with an increase in c-jun transcripts or other phenotypic characteristics of monocytic differentiation. By contrast, treatment of HL-60/vinc cells with okadaic acid, an inhibitor of serine/threonine protein phosphatases, induces c-jun transcription, growth arrest, and expression of the c-fms gene. Studies were also performed with an HL-60/vinc revertant (HL-60/vinc/R) line that has regained partial sensitivity to vincristine. The finding that HL-60/vinc/R cells respond to TPA with induction of a monocytic phenotype, but not c-jun expression, suggests that c-jun induction is not obligatory for monocytic differentiation. Other studies further demonstrate that the jun-B and fra-1 genes are induced by TPA in both HL-60/vinc and HL-60/vinc/R cells, whereas c-fos expression is attenuated in the HL-60/vinc line. Since TPA activates protein kinase C (PKC), we examined translocation of PKC from the cytosol to the membrane fraction. Although HL-60 and HL-60/vinc/R cells demonstrated translocation of PKC activity, this subcellular redistribution was undetectable in HL-60/vinc cells. Activity of the mitogen-activated protein kinase family with associated phosphorylation of c-Jun Y-peptide was markedly diminished in TPA-treated HL-60/vinc cells, but not in response to okadaic acid. Taken together, these findings suggest that vincristine resistance confers insensitivity to TPA-induced differentiation and can include defects in PKC-mediated signaling events and induction of jun/fos early response gene expression.
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PMID:Defective translocation of protein kinase C in multidrug-resistant HL-60 cells confers a reversible loss of phorbol ester-induced monocytic differentiation. 838 57

The DNA-dependent protein kinase (DNA-PK) phosphorylates a number of transcription factors. Here, we show that the DNA-PK modifies c-Jun in vitro and that serine residue 249 (Ser-249) is required for phosphorylation to occur. This residue corresponds to one of three sites of c-Jun that are phosphorylated in vivo and which negatively regulate c-Jun DNA binding in vitro. However, we find that phosphorylation of c-Jun by the DNA-PK does not interfere with DNA binding, indicating that phosphorylation at other sites is required for this effect. Mutagenesis of the phosphorylated region of c-Jun reveals that the primary amino acid sequence recognised by the DNA-PK consists of the sequence Ser-Gln, and that adjacent acidic residues potentiate kinase activity. Furthermore, when this site is placed within the context of a second protein, it confers DNA-PK directed phosphorylation upon that protein. Our findings will facilitate identification of DNA-PK phosphorylation sites in other transcription factors.
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PMID:c-Jun is phosphorylated by the DNA-dependent protein kinase in vitro; definition of the minimal kinase recognition motif. 846 13

Proteolytic remodeling of the extracellular matrix occurs normally during development and pathologically in arthritis, tumor metastasis, wound healing, and angiogenesis. The major extracellular matrix-degrading proteinases belong to the matrix metalloproteinase (MMP) and plasminogen activator gene families. Intracerebral injection of 72-kDa type IV collagenase (gelatinase A) opens the blood-brain barrier. During hemorrhagic brain injury or intracerebral injection of proinflammatory cytokines, endogenous production of 92-kDa type IV collagenase (gelatinase B) occurs. The gelatinase B gene contains a phorbol ester responsive region (TRE) that binds AP-1 proteins, including c-Fos/c-Jun dimer, the early immediate response gene products. Maximum production of gelatinase B in injury occurs between 16 and 24 h, making this a late effector gene. The serine proteinase, urokinase-type plasminogen activator (uPA), is also produced at that time. Gelatinases and plasminogen activators work in concert to disrupt basement membranes proteolytically. A similar process opens the blood-brain barrier after ischemic and hemorrhagic brain injury, leading to secondary vasogenic brain edema. Delayed damage by proteolytic cascade enzymes provides opportunities for treatment much later than had been thought possible. Potential treatments possible in this second therapeutic window include interfering with the genes that produce the MMPs or inhibiting the action of the gene products.
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PMID:Matrix metalloproteinases in brain injury. 859 11

Insulin activation of Ras is mediated by the plasma membrane targeting of the guanylnucleotide exchange factor SOS associated with the small adapter protein Grb2. SOS also lies in an insulin-stimulated feedback pathway in which the serine/threonine phosphorylation of SOS results in disassociation of the Grb2-SOS complex thereby limiting the extent of Ras activation. To examine the relative role of the mitogen-activated protein kinases in the feedback phosphorylation of SOS we determined the signaling specificity of insulin, osmotic shock, and anisomycin to activate the ERK (extracellular-signal regulated kinase) and JNK (c-Jun kinase) pathways. In Chinese hamster ovary cells expressing the human insulin receptor and murine 3T3L1 adipocytes, insulin specifically activated ERK with no significant effect on JNK, whereas anisomycin specifically activated JNK but was unable to activate ERK. In contrast, osmotic shock was equally effective in the activation of both kinase pathways. Insulin and osmotic shock, but not anisomycin, resulted in SOS phosphorylation and disassociation of the Grb2-SOS complex, demonstrating that the JNK pathway was not involved in the insulin-stimulated feedback uncoupling of the Grb2- SOS complex. Both the insulin and osmotic shock-induced activation of ERK was prevented by treatment of cells with the specific MEK inhibitor (PD98059). However, expression of dominant-interfering Ras (N17Ras) inhibited the insulin- but not osmotic shock-stimulated phosphorylation of ERK and SOS. These data demonstrate that activation of the ERK pathway, but not JNK, is responsible for the feedback phosphorylation and disassociation of the Grb2-SOS complex.
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PMID:SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. 862 28

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

Stimulation of [3H]serine-labeled A431 cells with tumor necrosis factor-alpha (TNFalpha) or bacterial sphingomyelinase (SMase) resulted in a rapid decrease (approximately 50% by 15 min) in cellular [3H]sphingomyelin content and generation of the lipid moiety [3H]ceramide, which remained elevated 60 min later. Sphingomyelin hydrolysis in response to TNFalpha or bacterial SMase resulted in a time-dependent decrease in the phosphorylation state of c-Jun protein, an effect that was also observed in cells treated with the membrane-permeable ceramide analogue N-hexanoylsphingosine (C6-ceramide). The rapid dephosphorylation of the c-Jun gene product in response to TNFalpha, SMase, or C6-ceramide was not observed in A431 cells treated with the serine-threonine phosphatase inhibitor okadaic acid. After the initial steps of previously described methods for the purification of a ceramide-activated protein phosphatase termed CAPP (Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C., and Hannun, Y. A. (1993) J. Biol. Chem. 268, 15523-15530), we obtained a cytosolic fraction from A431 cells that specifically dephosphorylated 32Pi-labeled c-Jun protein used as substrate in an immunocomplex phosphatase assay. Phosphatase activity in vitro was apparent only in the presence of ceramide (5 micro) and was specifically abrogated when okadaic acid (1 n) was included in the immunocomplex phosphatase assay. These results provide strong evidence for c-Jun as a downstream target for CAPP activated in response to post-TNF signaling in A431 cells.
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PMID:c-Jun is a downstream target for ceramide-activated protein phosphatase in A431 cells. 870 18

The c-Jun transcription factor contains a transactivation domain that belongs to the "acidic" type of transcription activator. To determine the secondary structure of the Jun activation domain, we synthesized a peptide corresponding to amino acids 61 to 98 of c-Jun. Jun N-terminal kinases are able to phosphorylate Ser-63 and Ser-73 in vivo, which dramatically increases the transactivation potential of Jun. As this phosphorylation event may influence the secondary structure, we synthesized a second peptide containing two phosphoserine groups instead of serine in positions 63 and 73. Secondary structure predictions did not show potential for the peptides to adopt any stable, dominating conformation. Both peptides were purified and analyzed by circular dichroism spectroscopy. The peptides appeared to be flexible and essentially unstructured in aqueous solution. At acidic pH, we observed a decrease in the negative ellipticity at 202 nm, suggesting that some ordered structure might be present under these conditions. alpha-Helical conformation, as a dominating secondary structure, was induced in the presence of trifluoroethanol, and there was no significant difference between the unphosphorylated and phosphorylated peptides.
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PMID:A c-Jun activation domain peptide and its corresponding phosphopeptide have potential to adopt alpha-helical conformation. 873 81

In Syrian hamster liver, treatment with 3-methylcholanthrene (3-MC) markedly induces an isozyme of cytochrome P450 (CYP), CYP2A8. To elucidate the mechanism of this induction, we studied the effect of okadaic acid (OA), an inhibitor of serine threonine protein phosphatases 1 and 2A, on 3-MC-induced CYP2A8 expression in primary cultures of Syrian hamster hepatocytes. The addition of OA to the cultured hepatocytes at a concentration of 1 nM potentiated 3-MC- (0.1 and 1 microM) induced expression of mRNA and protein of CYP2A8 and its associated coumarin 7-hydroxylase activity. In addition, OA not only induced c-fos and jun-D mRNA, components of transcription factor activator protein-1 (AP-1), with an increase in AP-1 binding activity in the nucleus, but also activated AP-1-dependent gene transcription in the hepatocytes. The dose-dependent effect of OA on 3-MC-induced CYP2A8 expression corresponded to that of OA on c-fos and jun-D mRNA induction and on the activation of AP-1-dependent gene transcription. The expression of c-fos and jun-D mRNA induced by OA preceded the expression of CYP2A8 mRNA potentiated by co-treatment with 3-MC and OA. Treatment with anisomycin and cycloheximide also potentiated 0.1 microM 3-MC-induced coumarin 7-hydroxylase activity, induced c-fos and jun-D mRNA expression, and activated AP-1-dependent gene transcription in the hepatocytes. Furthermore, 3-MC-induced CYP2A8 expression was potentiated in the hepatocytes transfected with c-Jun expression plasmid. These results suggest that AP-1, inducible by serine threonine protein kinase, may be one of the components of the signal transduction system from 3-MC to CYP2A8 gene expression.
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PMID:Okadaic acid potentiates 3-methylcholanthrene-induced CYP2A8 gene expression in primary cultures of Syrian hamster hepatocytes: possible involvement of activator protein-1. 879 94

Work from a number of laboratories has established a role for certain small GTP-binding proteins in controlling the enzymatic activity of a family of serine-threonine kinases known as mitogen-activated protein kinases (MAPKs). MAPKs have been classified into three subfamilies: extracellular signal-regulated kinases (ERKs), also known as MAPKs; c-Jun N-terminal kinases (JNKs); and p38 kinase. Whereas Ras controls the activation of MAPKs, we and others have recently observed that in certain cells, the small GTP-binding proteins Rac1 and Cdc42 but not Rho regulate the activity of JNKs. Furthermore, because Rac1 and Cdc42 but not Rho bind and activate a kinase known as Pak1, it has been suggested that Pak1 is the most upstream component of the pathway linking these GTPases to JNK. However, in both yeast and mammalian cells, Rho1p, a Rho homologue, and RhoA, respectively, directly interact with a number of proteins, including kinases related to protein kinase C. In addition, in yeast, Rho1p controls the activity of a MAPK cascade involved in bud formation. Considering this diversity of target molecules for small GTP-binding proteins, their likely tissue specific distribution, and the potential role for Rho in signaling to a kinase cascade, we decided to extend our initial analysis, exploring the ability of Ras and Rho-related GTP-binding proteins to activate MAPK or JNK in a variety of cell lines. We found that in the human kidney epithelial cell line, 293T, Cdc42 and all Rho proteins, RhoA, RhoB, and RhoC, but not Rac or Ras can induce activation of JNK. Furthermore, we provide evidence that signaling from Rho proteins to JNK in 293T cells does not involve Pak1. Taken together these findings demonstrate that Rho signals to JNK in a cell type-specific manner and suggest the existence of a novel, Pak1-independent signaling route communicating the Rho family of small GTP-binding proteins to the JNK pathway.
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PMID:The small GTP-binding protein rho activates c-Jun N-terminal kinases/stress-activated protein kinases in human kidney 293T cells. Evidence for a Pak-independent signaling pathway. 882 97


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