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)

Using polyacrylamide gel mobility shift assay we have detected a nuclear factor (NF-S) in a mouse mammary tumor cell line (GR) that binds to an upstream sequence domain (-766 to -737) near the 5'-end of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). Antibodies to the products of the Jun and Fos oncogenes interfered with the binding potential of this factor, indicating that the factor shares antigenic determinants with c-Jun/AP-1. In vitro translated c-Jun and c-Fos were also found to bind to the NF-S binding domain consisting of the sequence TGA(A/G)TCA that are known to be recognized by c-Jun/AP-1. Our results raise the possibility that the MMTV-LTR sequence element-766 to -737 by interacting with a Jun/Fos related protein play a role in MMTV transcription and/or the activation of int protooncogenes that are associated with murine mammary tumorigenesis.
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PMID:The interaction of a c-Jun/Fos related protein factor with the U3 sequences of the mouse mammary tumor virus LTR. 217 22

Marek's disease virus (MDV) is an avian herpesvirus that induces a variety of diseases, including T-cell lymphomas, in chickens. In latently infected, transformed lymphoid cells, very few viral transcripts or proteins are detected. We previously described a gene, meq (MDV EcoQ), which is persistently expressed in MDV-transformed tumor samples and cell lines. meq codes for a 339-amino-acid protein with a basic-leucine zipper domain near its N terminus and a proline-rich domain near its C terminus. The basic-leucine zipper domain shows homology with Jun/Fos family proteins, whereas the proline-rich domain resembles that of the WT-1 tumor suppressor protein. These structural features raise the possibility that Meq functions as a transcription factor in regulating viral latency or oncogenesis. In this report, we show that the proline-rich domain is a potent transcription activator when fused to the yeast (Saccharomyces cerevisiae) Gal4(1-147) DNA-binding domain. The transactivation activity maps to the C-terminal 130 amino acids, with the last 33 amino acids essential. In the absence of these 33 amino acids, a two-and-one-half proline-rich repeat structure was found to exhibit repression activity. We further show that Meq is able to dimerize not only with itself but also with c-Jun. Meq/c-Jun heterodimers bind to an AP1-like sequence in the meq promoter region with an affinity much greater than that of Meq/Meq or c-Jun/c-Jun homodimers. Cotransfection chloramphenicol acetyltransferase assays suggest that the Meq/c-Jun heterodimers can up-regulate Meq expression in both chicken embryo fibroblasts and F9 cells. Our data provide the first biochemical evidence that Meq is a transcriptional factor and identify c-Jun as one of Meq's interacting partners.
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PMID:Transactivation activity of Meq, a Marek's disease herpesvirus bZIP protein persistently expressed in latently infected transformed T cells. 776 61

Hepatitis B virus produces a small (154-amino acid) transcriptional transactivating protein, HBx, which is required for viral infection and has been implicated in virus-mediated liver oncogenesis. However, the molecular mechanism for HBx activity and its possible influence on cell proliferation have remained obscure. A number of studies suggest that HBx may stimulate transcription by indirectly activating transcription factors, possibly by influencing cell signaling pathways. We now present biochemical evidence that HBx activates Ras and rapidly induces a cytoplasmic signaling cascade linking Ras, Raf, and mitogen-activated protein kinase (MAP kinase), leading to transcriptional transactivation. HBx strongly elevates levels of GTP-bound Ras, activated and phosphorylated Raf, and tyrosine-phosphorylated and activated MAP kinase. Transactivation of transcription factor AP-1 by HBx is blocked by inhibition of Ras or Raf activities but not by inhibition of Ca(2+)- and diacylglycerol-dependent protein kinase C. HBx was also found to stimulate DNA synthesis in serum-starved cells. The hepatitis B virus HBx protein therefore stimulates Ras-GTP complex formation and promotes downstream signaling through Raf and MAP kinases, and may influence cell proliferation.
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PMID:Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. 793 54

Growth factors, phorbol esters, and oncogenes such as ras, src, and sis are believed to stimulate c-Jun transcriptional activation by inducing increased phosphorylation at two serine residues (S63 and S73) within the N-terminal transactivation domain. Although S63 and S73 are conserved in the mutant v-Jun oncoprotein, they are not phosphorylated by two enzymes which target the corresponding residues in c-Jun in vitro; namely a partially purified c-Jun kinase from TPA-stimulated U937 cells and purified p54 mitogen activated protein (MAP) kinase. In addition, v-Jun activates transcription more strongly than c-Jun when fused to the Gal4 DNA-binding domain, and transcriptional activation by Gal4-v-Jun is unaffected when S63, S73, or both, are replaced with non-phosphorylatable alanine residues, amino acid substitutions which severely impair transcriptional activation by Gal4-c-Jun. The novel biochemical and transcriptional properties of v-Jun result from deletion of a 27 amino acid segment, termed delta, which is important for transforming activity. On the basis of these results we propose that unlike c-Jun, v-Jun transcriptional activation is independent of positive regulatory phosphorylation and that this may contribute to oncogenesis by v-Jun.
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PMID:Transcriptional activation by the v-Jun oncoprotein is independent of positive regulatory phosphorylation. 803 19

The role of the ubiquitin-dependent proteolysis system in c-Jun breakdown was investigated. Using in vitro experiments and a novel in vivo assay that utilizes molecularly-tagged ubiquitin and c-Jun proteins, it was shown that c-Jun, but not its transforming counterpart, retroviral v-Jun, can be efficiently multiubiquitinated. Consistently, v-Jun has a longer half-life than c-Jun. Mutagenesis experiments indicate that the reason for the escape of v-Jun from multiubiquitination and its resulting stabilization is the deletion of the delta domain, a stretch of 27 amino acids that is present in c-Jun but not in v-Jun. c-Jun sequences containing the delta domain, when transferred to the bacterial beta-galactosidase protein, function as a cis-acting ubiquitination and degradation signal. The correlation between transforming ability and the escape from ubiquitin-dependent degradation described here suggests a novel route to oncogenesis.
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PMID:Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain. 808 46

To be able to elucidate the function of cyclin D1 in the control of cell cycle progression and its role as an oncogene in tumorigenesis, it is of paramount importance to understand the mechanisms involved in the regulation of its expression. In the present study, we have cloned the human cyclin D1 gene and analysed the structure and function of 3kb of its 5'-flanking region. Several regulatory regions involved in both basal level and serum-induced expression were identified, two of which turned out to be of particular interest. One of these regions is involved in serum induction and is located 848-944 bp upstream of the initiation site. In agreement with this result, in vivo footprinting revealed a novel, strongly inducible protein binding site around positions -928 to -921. A second constitutively occupied binding site was mapped to a potential CRE at position -52. Cotransfection experiments showed that the cyclin D1 promoter is inducible by c-Jun, and that this induction is mediated predominantly through the protected putative CRE at -52.
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PMID:Inducible regulatory elements in the human cyclin D1 promoter. 820 58

Nuclear levels of c-Jun, JunB, c-Fos, and LRF-1 (liver regeneration factor) are high for a large fraction of the G1 phase in regenerating liver and mitogen-stimulated hepatic cells. Previously, JunB was regarded as a less potent transcriptional activator than c-Jun that could also function as a repressor. However, we found that, like c-Jun, JunB alone or LRF-1/JunB strongly transactivates a cAMP-responsive promoter. Unlike c-Jun, JunB represses several AP-1 or activator of transcription factor site-containing promoters, and this inhibition is greatly enhanced in the presence of LRF-1. Here, we identify separate regions of JunB required for trans-activation and repression of these promoters. Deletion analysis shows that the region involved in trans-activation function is highly conserved among all Jun family members and corresponds to activator domain (A1) of c-Jun. In contrast, repression is maximal in the presence of both the DNA-binding domain and a region proximal to the basic region that is highly divergent among Jun proteins. Functional distinctions between Jun proteins during induction of the growth response and tumorigenesis may be accounted for by promoter-specific activation and repression mediated by regional differences in Jun family proteins.
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PMID:Promoter-specific trans-activation and inhibition mediated by JunB. 833 92

Urokinase-type plasminogen activator (uPA) is an extracellular protease and expressed in various cells that exhibit dynamic changes in cell morphology, suggesting a link between cytoskeletal reorganization (CSR) and uPA expression. CSR can be induced by pharmacological agents, such as by colchicine for microtubule cytoskeleton and by cytochalasin for microfilament cytoskeleton. Using these agents, we previously showed that CSR induced the uPA gene in LLC-PK1 cells independently of the protein kinase C and cAMP-dependent protein kinase. Here we show that the induction of the uPA gene by CSR is mediated by the activation of c-Jun which interacts with an AP-1-like site located 2 kb upstream of the uPA gene. 12-O-tetradecanoylphorbol 13-acetate (TPA) induces the uPA gene through the same elements, but additionally utilizes an adjacent PEA3 element and induces c-fos. Furthermore, CSR induces a greater accumulation and a more pronounced phosphorylation of c-Jun than TPA induction. AP-1 is a positive regulator of growth and oncogenesis, and CSR is an integral part of these processes. Our results provide a view how CSR and AP-1 could be coupled in these processes. We also show that TPA and CSR act synergistically, suggesting a model where an initial activation signal could be amplified by CSR.
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PMID:Cytoskeletal reorganization and TPA differently modify AP-1 to induce the urokinase-type plasminogen activator gene in LLC-PK1 cells. 834 15

A specific viral oncogenic mechanism has not been shown for hepatitis B virus (HBV), although persistent HBV infection has been strongly associated with the development of hepatocellular carcinoma (HCC). Most HCCs in HBV carriers contain integrated viral sequences in host DNA and this raises the question of whether such integrations ever contribute to oncogenesis. HBV does contain a gene (designated the hbx gene) which encodes a transcriptional trans-activator protein capable of activating homologous and heterologous regulatory sequences. Hbx has been detected in some human HCC with HBV integrations and the expressed hbx protein appears to have transcriptional transactivating activity. These findings raise the possibility that hbx expression could contribute to hepatocarcinogenesis by activating cellular genes that could contribute to oncogenicity. The possibility that the hbx protein may activate certain protooncogenes was investigated and we found that hbx can activate the protooncogene c-jun promoter. c-Jun was found to be expressed at a very low level in normal liver tissue but at high levels in HCCs of HBV-infected patients.
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PMID:Activation of protooncogene c-jun by the X protein of hepatitis B virus. 839 Jul 62

The retroviral oncogene v-jun and its cellular counterpart code for proteins that function as major components of the transcription factor complex AP-1. Jun proteins bind to the AP-1 consensus sequence as homodimers or heterodimers with members of the Fos protein family. This report compares the ability of viral and cellular Jun proteins (v-Jun and c-Jun) to activate transcription and to stimulate DNA synthesis. The effect of amino acid substitutions on cellular transformation is also described. In F9 cells c-Jun is a more effective transactivator than v-Jun, which carries two amino acid substitutions in the carboxy-terminal region that together down-regulate transactivation. The delta deletion, present in the amino-terminal region of v-Jun, does not affect transactivation in F9 cells; however, it does modulate the stimulation of DNA synthesis. When delta is deleted, the amino acid substitutions are without consequence on DNA synthesis. In the presence of delta the amino acid substitutions down-regulate DNA synthesis. Deletion of the Jun transactivation domain, which is required for cellular transformation, abolishes both transactivation and stimulation of DNA synthesis. We conclude that transformation, transactivation and stimulation of DNA synthesis all depend on the presence of the transactivation domain. The three functions are, however, not tightly correlated, and further work is needed to define the role of the biochemical activities of Jun in oncogenesis.
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PMID:Amino acid substitutions modulate the effect of Jun on transformation, transcriptional activation and DNA replication. 847 38


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