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: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA topoisomerase II (topo II) is an essential nuclear enzyme which catalyzes the interconversions of various forms of DNA. As predicted from the human topo II cDNA, the enzyme contains a potential leucine zipper protein dimerization motif. We therefore tested whether topo II could enter protein-protein interactions with other better characterized leucine zipper-containing proteins and determined if these interactions could modify topo II enzymatic activity in vitro. By far Western analyses, a large C-terminal fragment of human topo II was shown to interact with the DNA binding and dimerization regions of either cAMP response element binding protein (CREB) or the activating transcription factor-2. The C-terminal topo II fragment also interacted with full-length c-Jun, but not with full-length c-Fos. Using CREB as a prototype, the effect of this interaction on various topo II catalytic activities was assessed in vitro. CREB, at a 1- to 10-fold molar excess relative to topo II, inhibited site-specific DNA cleavage activity on a 242-base pair fragment of the human alpha-glycoprotein hormone subunit gene promoter. Very high CREB concentrations (400-fold excess) apparently inhibited topo II DNA relaxation activity, but this result was likely a direct effect of CREB on the topology of the DNA substrate. More interestingly, a 10-fold molar excess of CREB stimulated topo II decatenation activity, the essential function of this enzyme in cell division. This stimulatory effect could also be elicited by c-Jun, which interacts with topo II, but not by c-Fos, which does not bind topo II in our in vitro assay. Since similar amounts of CREB reduced the abundance of topo II DNA cleavage products from the human alpha-CG promoter yet also stimulated decatenation activity, it can be concluded that either: 1) CREB stimulated the religation rate of topo II; or 2) CREB directed topo II to a new cleavage site present on the decatenation substrate but not present on the limited alpha-CG promoter. The structural requirements for topo II protein-protein interactions were also investigated. Site-directed mutations which destroyed the putative topo II leucine zipper did not disrupt topo II protein-protein interactions. Since the putative leucine zipper in topo II does not appear to mediate protein-protein interactions, we propose that an alternate as yet uncharacterized structure is involved in the association of topo II with itself and other regulatory proteins.
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PMID:Modification of DNA topoisomerase II activity via direct interactions with the cyclic adenosine-3',5'-monophosphate response element-binding protein and related transcription factors. 838 55

The alpha subunit gene encodes a common subunit shared by all glycoprotein hormones. This single copy gene is expressed in pituitary gonadotropes and thyrotropes of all mammals and in placental trophoblasts of primates and horses. Tandem cAMP response elements (CREs) in the promoter of the human gene are key mediators of this pattern of cell-specific expression. Replacing the palindromic CREs with non-primate variant CREs significantly attenuated activity in trophoblasts but not in gonadotropes. Furthermore, proteins binding the palindromic CRE cross-reacted with antibodies for CREB, CREM, ATF1, ATF2, and c-Jun, while proteins binding the variant CRE cross-reacted only with ATF2 and c-Jun antibodies. The data suggest that ATF2 and c-Jun can activate transcription through the CREs in gonadotropes but not in trophoblasts. Additional analyses indicated that while promoters with either palindromic or variant CREs have similar overall activity in gonadotropes, the variant CREs make a much smaller contribution to promoter activity than their palindromic counterparts. The weaker contribution of the variant CREs is compensated by the activity of two upstream elements present in the promoter. This compensation probably occurs through an indirect mechanism, as the binding affinity of proteins to the CRE is not influenced by the presence of these upstream elements.
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PMID:The cAMP response elements of the alpha subunit gene bind similar proteins in trophoblasts and gonadotropes but have distinct functional sequence requirements. 894 Jan 85

The Oligodendrocyte-Myelin glycoprotein gene (OMgp) is placed within an intron of the NF1 gene. Neurofibromin, the product of NF1, acts as a RasGAP and suppresses growth; inactivating mutations in NF1 lead to neurofibromatosis type 1. We report that OMgp also has growth suppressive effects and downregulates mitogenic signaling pathways closely related to those influenced by neurofibromin. Overexpression of OMgp alters mitogenic signaling in NIH3T3 fibroblasts. Cells overexpressing OMgp grow more slowly in serum compared to controls and show a partial G1 block upon cell cycle analysis. PDGF is the primary mitogen for fibroblasts in serum. Overexpression of OMgp alters PDGF signaling in fibroblasts which results in a block of mitogenic signaling. PDGF induced activation of c-Src is blocked, as is the induction of c-Myc and c-Fos, while tyrosine phosphorylation of the PDGFbeta receptor, PLCgamma1 and induction of c-Jun are intact. Although a number of genes embedded within other genes have been described, the biological significance of this arrangement remains unknown. We demonstrate here that structurally unrelated products of two such genes may exercise closely related functions. Our data also raise the possibility of a role for OMgp in disorders of cell proliferation such as NF1.
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PMID:The OMgp gene, a second growth suppressor within the NF1 gene. 956 19

The CD5 lymphocyte surface glycoprotein is a coreceptor involved in the modulation of Ag-specific receptor-mediated activation and differentiation signals. The molecular basis for its modulatory properties is not yet well understood. In the present study we describe early biochemical events triggered by CD5 stimulation, which include the phosphatidylcholine-specific phospholipase C (PC-PLC)-dependent activation of acidic sphingomyelinase (A-SMase) in normal and lymphoblastoid T and B cells. The functional coupling of PC-PLC and A-SMase is demonstrated by the abrogation of A-SMase activation by 1) xanthogenate tricyclodecan-9-yl (D609), a selective inhibitor of PC-PLC, and 2) replacement of several C-terminal serine residues (S458, S459, and S461) present in the cytoplasmic tail of CD5 that are known to be critical for PC-PLC activation. Additionally, we demonstrate that activation of protein kinase C-zeta (PKC-zeta) and members of the mitogen-activated protein kinase (MAPK) cascade (MAPK kinase and c-Jun NH2-terminal kinase), but not the NF-kappaB, are downstream events of the CD5 signaling pathway. A-SMase, PKC-zeta, and MAPK family members are key mediators of cell responses as diverse as proliferation, differentiation, and growth arrest and may contribute to CD5-mediated modulation of TCR or BCR signaling.
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PMID:Signaling through CD5 involves acidic sphingomyelinase, protein kinase C-zeta, mitogen-activated protein kinase kinase, and c-Jun NH2-terminal kinase. 1022 86

The aim of these studies was to elucidate a role for epidermal growth factor (EGF) signaling in the transcriptional regulation of the glycoprotein hormone alpha subunit gene, a subunit of chorionic gonadotropin. Studies examined the effects of EGF and the adenylate cyclase activator forskolin on the expression of a transfected alpha subunit reporter gene in a human choriocarcinoma cell line (JEG3). At maximal doses, administration of EGF resulted in a 50% increase in a subunit reporter activity; forskolin administration induced a fivefold activation; the combined actions of EGF and forskolin resulted in synergistic activation (greater than eightfold) of the alpha subunit reporter. Mutagenesis studies revealed that the cyclic AMP response elements (CRE) were required and sufficient to mediate EGF-forskolin-induced synergistic activation. The combined actions of EGF and forskolin resulted in potentiated activation of extracellular signal-regulated kinase (ERK) enzyme activity compared with EGF alone. Specific blockade of ERK activation was sufficient to block EGF-forskolin-induced synergistic activation of the alpha subunit reporter. Pretreatment of JEG3 cells with a p38 mitogen-activated protein kinase inhibitor did not influence activation of the alpha reporter. However, overexpression of c-Jun N-terminal kinase (JNK)-interacting protein 1 as a dominant interfering molecule abolished the synergistic effects of EGF and forskolin on the alpha subunit reporter. CRE binding studies suggested that the CRE complex consisted of CRE binding protein and EGF-ERK-dependent recruitment of c-Jun-c-Fos (AP-1) to the CRE. A dominant negative form of c-Fos (A-Fos) that specifically disrupts c-Jun-c-Fos DNA binding inhibited synergistic activation of the alpha subunit. Thus, synergistic activation of the alpha subunit gene induced by EGF-forskolin requires the ERK and JNK cascades and the recruitment of AP-1 to the CRE binding complex.
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PMID:Role of the cyclic AMP response element binding complex and activation of mitogen-activated protein kinases in synergistic activation of the glycoprotein hormone alpha subunit gene by epidermal growth factor and forskolin. 1077 23

Thrombospondin-1 (TSP-1) is a homotrimeric glycoprotein synthesized in a variety of normal and transformed cells, and secreted into the extracellular matrix. Based on its known effects on the tumor and endothelial cells, TSP-1 was implicated in the tumor growth and metastasis. In the present study, we have demonstrated the expression of TSP-1 in the human hepatocarcinoma cell lines. TSP-1 was detected in human hepatocarcinoma SK-HEP-1, Hep 3B and immortalized human liver Chang cells. Using two different cell lines, SK-HEP-1 and Hep 3B cells, we have studied effects of phorbol 12-myristate 13-acetate (PMA) on TSP-1 expression. TSP-1 synthesis was stimulated by PMA in both cell lines. When the cells were treated with PMA, the TSP-1 mRNA started to increase at 30 min and reached the maximal level at 6 h. TSP-1 induction by PMA was completely inhibited by the pre-treatment of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a potent protein kinase C inhibitor. A TSP-1 promoter-luciferase reporter gene was transcriptionally activated by PMA, as well as by the expression of c-Jun. Among three putative AP-1 recognition sites on the TSP-1 promoter, a deletion of the 1st and 2nd sites caused loss of PMA-induced upregulation, while the 3rd site deletion showed no effect. In subsequent experiments, both the recombinant c-Jun and nuclear proteins induced by PMA have a stronger binding affinity for the 2nd AP-1 recognition site than the 1st and 3rd ones. Our study demonstrated that TSP-1 could be expressed and secreted by human hepatoma cell lines and its expression could be effectively regulated by PMA. We also suggest that AP-1 binding activity through the protein kinase C activation is a critical event for the TSP-1 gene expression and consequently affects production and processing of the protein.
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PMID:Expression of thrombospondin-1 in human hepatocarcinoma cell lines and its regulation by transcription factor Jun/AP-1. 1121 60

Human immunodeficiency virus type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 as coreceptors for entry. It was recently demonstrated that HIV-1 glycoprotein 120 (gp120) elevated calcium and activated several ionic signaling responses in primary human macrophages, which are important targets for HIV-1 in vivo. This study shows that chemokine receptor engagement by both CCR5-dependent (R5) and CXCR4-dependent (X4) gp120 led to rapid phosphorylation of the focal adhesion-related tyrosine kinase Pyk2 in macrophages. Pyk2 phosphorylation was also induced by macrophage inflammatory protein-1beta (MIP-1beta) and stromal cell-derived factor-1alpha, chemokine ligands for CCR5 and CXCR4. Activation was blocked by EGTA and by a potent blocker of calcium release-activated Ca++ (CRAC) channels, but was insensitive to pertussis toxin (PTX), implicating CRAC-mediated extracellular Ca++ influx but not Galpha(i) protein-dependent mechanisms. Coreceptor engagement by gp120 and chemokines also activated 2 members of the mitogen-activated protein kinase (MAPK) superfamily, c-Jun amino-terminal kinase/stress-activated protein kinase and p38 MAPK. Furthermore, gp120-stimulated macrophages secreted the chemokines monocyte chemotactic protein-1 and MIP-1beta in a manner that was dependent on MAPK activation. Thus, the gp120 signaling cascade in macrophages includes coreceptor binding, PTX-insensitive signal transduction, ionic signaling including Ca++ influx, and activation of Pyk2 and MAPK pathways, and leads to secretion of inflammatory mediators. HIV-1 Env signaling through these pathways may contribute to dysregulation of uninfected macrophage functions, new target cell recruitment, or modulation of macrophage infection.
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PMID:HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. 1169 70

Clusterin is a ubiquitous secretory glycoprotein that is known to suppress certain forms of apoptosis. Since apoptosis and proliferation are two opposing cellular events, it remains unclear if clusterin has any effect on cellular proliferation. The objective of the present study was to examine the effects of clusterin on proliferation in a prostate cancer cell line, LNCaP. We found that clusterin inhibited EGF-mediated proliferation in these cells, as measured by (3)H-thymidine incorporation and by cell counting. Clusterin did not bind with EGF nor did it block phosphorylation of the EGF receptor. Treatment of LNCaP cells with EGF resulted in a transient increase in the expression of both c-Fos and c-Jun. Addition of clusterin to these cultures significantly down-regulated the protein level of c-Fos, but not c-Jun. These results demonstrated a novel biological role for clusterin. Clusterin is not only anti-apoptotic but also anti-proliferative. The anti-proliferative event maybe associated with a down-regulation of c-Fos.
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PMID:A novel anti-proliferative property of clusterin in prostate cancer cells. 1240 41

Ependymin (EPN) is a goldfish brain neurotrophic factor previously shown to function in a variety of cellular events related to long-term memory formation and neuronal regeneration. CMX-8933, an 8-amino-acid synthetic peptide fragment of EPN, was designed for aiding an investigation of the biological properties of this glycoprotein. We reported from previous studies that treatment of mouse neuroblastoma (NB2a) cultures with CMX-8933 promotes activation of transcription factor AP-1, a characteristic previously associated with the following full-length neurotrophic factors: nerve growth factor, neurotropin-3, and brain-derived neurotrophic factor. The CMX-8933-activated AP-1 specifically bound an AP-1 consensus probe and appeared to contain c-Jun and c-Fos protein components in antibody supershift experiments. Because AP-1 influences a variety of positive and negative cellular processes, determined in part by its exact protein composition and mechanism of activation, we extended these initial AP-1 observations in the current study to confirm the identity of the CMX-8933-activated c-Jun and c-Fos components. CMX-8933 increases the enzymatic activity of c-Jun N-terminal kinase (JNK), increases the phosphorylation of JNK and c-Jun proteins, and increases the cellular titers of c-Jun and c-Fos mRNAs. Furthermore, the AP-1 activated by CMX-8933 is functional, insofar as it transactivates both synthetic and natural AP-1-dependent reporter plasmids. Inhibition studies indicate that activation of the 8933-induced AP-1 occurs via the mitogen-activated protein kinase pathway. These data are in agreement with the recently proposed model for the conversion of short- to long-term synaptic plasticity and memory, in which a JNK-activated transcription factor AP-1, containing c-Jun and c-Fos components, functions at the top of a hierarchy of transcription factors known to regulate long-term neural plasticity.
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PMID:A peptide fragment of ependymin neurotrophic factor uses protein kinase C and the mitogen-activated protein kinase pathway to activate c-Jun N-terminal kinase and a functional AP-1 containing c-Jun and c-Fos proteins in mouse NB2a cells. 1269 7

The dystrophin glycoprotein complex has been proposed to be involved in signal transduction. Here we have shown that laminin binding causes syntrophin to recruit Rac1 from the rabbit skeletal muscle. Laminin-Sepharose and syntrophin-Sepharose bind a protein complex containing Rac1 from the muscle membranes. The presence of heparin, which inhibits laminin interactions, prevents recruitment of Rac1. The dystrophin glycoprotein complex recruits Rac1 via syntrophin through a Grb2.Sos1 complex. A syntrophin antibody also prevents recruitment of Rac1, suggesting that the signaling complex requires syntrophin. PAK1 is in turn bound by Rac1. c-Jun NH2-terminal kinase-p46 is phosphorylated and activated only when laminin is present, and the p54 isoform is activated when laminin is depleted or binding is inhibited with heparin. In the presence of laminin, c-Jun is activated in both skeletal muscle microsomes and in C2C12 myoblasts, and proliferation increases in C2C12 myoblasts. We postulate that this pathway signals muscle homeostasis and hypertrophy.
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PMID:Skeletal muscle signaling pathway through the dystrophin glycoprotein complex and Rac1. 1288 73


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