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 mitogenic action of cytokines such as epidermal growth factor (EGF) or platelet derived growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor-induced and oncogenic activation of Ras involve the conversion of Ras from the GDP-bound (D-Ras) to the GTP-bound (T-Ras) forms. T-Ras activates a network of protein kinases including c-Mos, c-Raf-1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c-Jun, c-Myc and c-Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the conversion of T-Ras to D-Ras. A series of small NF1 fragments, which bind T-Ras, as well as truncated forms of derivatives of c-Raf-1, c-Jun and c-Myc, are capable of blocking the T-Ras-activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T-Ras-associated tumors, which represent more than 30% of total human carcinomas.
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PMID:Regulation of the Ras signalling network. 794 77

Previous studies have shown that structurally diverse tumor promoters can modulate protein kinases involved in signal transduction. In this study, we show that palytoxin, a potent non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor promoter, induces a signaling pathway leading to the activation of the stress-activated protein kinases/c-Jun N-terminal kinases (JNK) in Swiss 3T3 fibroblasts. Treatment of cells with doses as low as 0.1 mN palytoxin results in significant activation of JNK. In contrast to epidermal growth factor, which induces a transient activation of JNK in Swiss 3T3 cells, palytoxin causes prolonged enzyme activation. Since stimulation of ion flux appears to play an important role in the mechanism of action of palytoxin in other systems, we investigated the role of sodium and calcium in the activation of JNK: (a) our results show that incubation of Swiss 3T3 cells in a sodium-free medium dramatically reduced the magnitude of JNK activation by palytoxin; and (b) we found that the sodium ionophore gramicidin activates JNK. Together, these results suggest that sodium influx, which is a hallmark of palytoxin action, may play a key role in the activation of JNK by palytoxin. Our results indicate that calcium influx is not necessary or sufficient for palytoxin-induced activation of JNK. In contrast to palytoxin, the TPA-type tumor promoter phorbol 12,13-dibutyrate and the non-TPA-type tumor promoters thapsigargin and okadaic acid do not appear to activate JNK in this system. In contrast to phorbol 12,13-dibutyrate, palytoxin does not activate the p42/p44 mitogen-activated protein kinases. Our results demonstrate that Swiss 3T3 fibroblasts, palytoxin can activate a protein kinase signaling pathway that is distinct from that activated by the prototypical phorbol ester tumor promoters and other potent skin tumor promoters.
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PMID:Activation of stress-activator protein kinase/c-Jun N-terminal kinase by the non-TPA-type tumor promoter palytoxin. 856 84

Phosphorylation of c-Jun was stimulated in primary cultured rat liver parenchymal cells by treatment with a coplanar polychlorinated biphenyl congener, 3,3'4,4'5-pentachlorobiphenyl (PenCB), as well as by epidermal growth factor, but was not stimulated by the non-coplanar form. However, the amount of c-Jun mRNA did not increase with PenCB treatment. PenCB may activate a signal-transducing pathway consisting of protein kinases.
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PMID:Phosphorylation of c-Jun stimulated in primary cultured rat liver parenchymal cells by a coplanar polychlorinated biphenyl. 861 Nov 67

We previously reported that introduction of H-ras oncogene decreases the epidermal growth factor (EGF) binding activity to cell surface EGF receptor in mouse Balb/3T3. In this study, we have further isolated four H-ras transfectants, four v-myc transfectants and three both H-ras and v-myc (H-ras/v-myc) transfectants of mouse Balb/3T3 cells. In comparison with introduction of v-myc alone or both H-ras and v-myc oncogene, introduction of H-ras alone resulted in a loss of [125I]EGF binding activity to the cell surface EGF receptor. RT-PCR analysis also showed much lower levels of EGF receptor gene expression in H-ras transfectants compared to that of parental untransformed cells (Balb-Neo1), v-myc and H-ras/v-myc transfectants. Our results demonstrated the activated binding of a transcription factor, Stat1 p84/p91, which directly interacts with EGF receptor, to c-sis-inducible element (SIE) in both v-myc and H-rs/v-myc transfectants, but not in H-ras transfectants. Among transcription factors which we have analysed, activator protein 1 (AP-1) but not SP-1 was modulated by H-ras. Gel shift assays demonstrated the mobility pattern of TPA-responsive element (TRE) binding complex with AP-1 derived from H-ras transfectants migrated faster than those from Balb-Neo1, v-myc and H-ras/v-myc. Expression of c-Jun and Fra-1 was increased more than threefold in H-ras transfectants compared with Balb-Neo1, v-myc and H-ras/v-myc transfectants, but that of c-Fos, Jun B and SP-1 was unchanged. Both transient and permanent expression of H-ras enhanced AP-1 activity in mouse cells, but further co-introduction of dominant negative c-jun mutant encoding a transcriptionally inactive product inhibited the H-ras dependent AP-1 induction. Transfection of the dominant negative c-jun mutant also restored down-regulation of EGF binding by activated H-ras oncogene. Down-regulation of EGf receptor by activated H-ras and the possible involvement of a transcription factor, AP-1 will be discussed.
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PMID:Regulation of epidermal growth factor receptor by activated H-ras and V-myc oncogenes in mouse Balb/3T3 cells: possible roles of AP-1. 862 82

The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respectively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrinsic tyrosine kinase of ErbB-3 is catalytically impaired. By using interleukin-3-dependent cells that ectopically express the three ErbB proteins or their combinations, we found that ErbB-3 is devoid of any biological activity but both ErbB-1 and ErbB-2 can reconstitute its extremely potent mitogenic activity. Transactivation of ErbB-3 correlates with heterodimer formation and is reflected in receptor phosphorylation and the transregulation of ligand affinity. Inter-receptor interactions enable graded proliferative and survival signals: heterodimers are more potent than homodimers, and ErbB-3-containing complexes, especially the ErbB-2/ErbB-3 heterodimer, are more active than ErbB-1 complexes. Nevertheless, ErbB-1 signaling displays dominance over ErbB-3 when the two receptors are coexpressed. Although all receptor combinations activate the mitogen-activated protein kinases ERK and c-Jun kinase, they differ in their rate of endocytosis and in coupling to intervening signaling proteins. It is conceivable that combinatorial receptor interactions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase-defective ErbB-3.
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PMID:Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. 866 53

Thrombin is a potent modulator of vascular tone and vascular smooth muscle cell (VSMC) mitogenesis. Early studies from other laboratories demonstrated that cyclic AMP (cAMP) antagonizes the mitogenic effects of platelet-derived growth factor and epidermal growth factor by inhibiting the extracellular signal-regulated protein kinases (ERKs; p42, p44) group of mitogen-activated protein kinases (MAPKs) in several cell types. This report examines the role of ERKs and Jun N-terminal kinase 1 (JNK1) groups of mitogen-activated protein kinases in thrombin-induced DNA synthesis in VSMCs using agents such as forskolin and dibutyrylcyclic AMP that increase intracellular cAMP levels. Both agents significantly inhibited thrombin-stimulated DNA synthesis in VSMCs. These agents, however, had no effect on thrombin induction of ERKs activation and c-Fos expression, suggesting divergence of the latter two events from the growth-signaling events of thrombin that are sensitive to inhibition by cAMP. Thrombin activated JNK1 and induced c-Jun expression in VSMCs in a time-dependent manner. In contrast to ERKs and c-Fos, thrombin-induced JNK1 activation and c-Jun expression were sensitive to inhibition by forskolin, suggesting an association of these events with thrombin-stimulated growth in these cells. Thrombin also increased AP-1 activity, and this response was significantly blunted by forskolin. Together, these results demonstrate a correlation between JNK1 activation and c-Jun expression by thrombin and their association with the mitogenic signaling events of thrombin in VSMCs.
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PMID:Cyclic AMP inhibition of thrombin-induced growth in vascular smooth muscle cells correlates with decreased JNK1 activity and c-Jun expression. 870 35

Many growth factors and agonists for G protein-coupled receptors activate mitogen-activated protein (MAP) kinase pathways, including the extracellular signal-regulated kinase (ERK) pathway and the c-Jun kinase (JNK) pathway. Transient transfection of dominant negative and constitutively active pathway components in COS-7 cells shows that two G protein subunits, Galpha12 and Galpha13, inhibit the ERK pathway and stimulate the JNK pathway. Constitutively active (GTPase-deficient) Galpha12 and Galpha13 both inhibit ERK pathway activation by epidermal growth factor. A Galpha13/alphaz chimera, which responds to stimulation by Gi-coupled receptors, mediates inhibition of ERK via such a receptor, the dopamine-2 receptor. In addition, expression of a dominant negative mutant of the GTPase, Cdc42, blocks activation of the JNK pathway by Galpha12 and Galpha13 but does not alter inhibition of ERK activation by the same Galpha proteins; conversely, mutationally activated Cdc42 stimulates the JNK pathway but has no effect on the ERK pathway. Our results show that different mechanisms mediate two effects of Galpha12 and Galpha13: the ERK pathway inhibition is mediated at the level of MAP kinase kinase in a Ras- and Raf-independent fashion, whereas the JNK pathway stimulation is mediated by Cdc42.
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PMID:Galpha12 and Galpha13 regulate extracellular signal-regulated kinase and c-Jun kinase pathways by different mechanisms in COS-7 cells. 870 75

Studies were undertaken to determine the effect of the Ras suppressor Rsu-1 on Ras signal transduction pathways in two different cell backgrounds. An expression vector containing the mouse rsu-1 cDNA under the control of a mouse mammary tumor virus promoter was introduced into NIH 3T3 cells and the pheochromocytoma cell line PC12. Cell lines developed in the NIH 3T3 background expressed p33rsu-1 at approximately twice the normal endogenous level. However, PC12 cell clones which expressed p33rsu-1 at an increased level in a regulatable fashion in response to dexamethasone were isolated. Analysis of proteins involved in regulation of Ras and responsive to Ras signal transduction revealed similar changes in the two cell backgrounds in the presence of elevated p33rsu-1. There was an increase in the level of SOS, the guanine nucleotide exchange factor, and an increase in the percentage of GTP-bound Ras. In addition, there was an increase in the amount of p120 Ras-specific GTPase-activating protein (GAP) and GAP-associated p190. However, a decrease in Ras GTPase-activating activity was detected in lysates of the Rsu-1 transfectants, and immunoprecipitated p120 GAP from the Rsu-1 transfectants showed less Ras GTPase-activating activity than GAP from control cells. Activation of Erk-2 kinase by growth factor and tetradecanyol phorbol acetate was greater in the Rsu-1 transfectants than in control cells. However, c-Jun amino-terminal kinase activity (Jun kinase) was not activatable by epidermal growth factor in Rsu-1 PC12 cell transfectants, in contrast to the PC12 vector control cell line. Transient expression of p33rsu-1 in Cos1 cells following cotransfection with either hemagglutinin-tagged Jun kinase or hemagglutinin-tagged Erk-2 revealed that Rsu-1 expression inhibited constitutive Jun kinase activity while enhancing Erk-2 activity. Detection of in vitro binding of Rsu-1 to Raf-1 suggested that in Rsu-1 transfectants, increased activation of the Raf-1 pathway occurred at the expense of activation of signal transduction leading to Jun kinase. These results indicate that inhibition of Jun kinase activation was sufficient to inhibit Ras transformation even in the presence of activated Erk-2.
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PMID:Increased expression of the Ras suppressor Rsu-1 enhances Erk-2 activation and inhibits Jun kinase activation. 881 60

Expression of the ovine P-450 side-chain cleavage enzyme gene (CYP11A1) is stimulated by epidermal growth factor (EGF) through a pathway that involves c-Jun in JEG-3 placental cells. Growth factor signaling involves ras-dependent and ras-independent signaling pathways, which in turn regulate gene transcription through related but distinct mitogen-activated protein kinase pathways (MAPKs) including the extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs). We investigated the intracellular signaling pathways governing EGF induction of the CYP11A1 promoter. EGF stimulation of the CYP11A1 promoter (4-fold) was reduced 60% by a dominant negative mutant of ras (N17), and 30-40% by antisense ras. EGF induced both ERK and SAPK activity in JEG-3 cells. EGF-induced CYP11A1 promoter activity was reduced 60% by the MEK1 inhibitor PD098059 and 50% by a dominant negative mutant of the ERK-specific regulator MEK1. In contrast, dominant negative mutants of the SAPK-specific activator, SEK1, induced a further increase in EGF-induced CYP11A1 promoter activity. Constitutively active mutants of ras (V12 or L61) increased CYP11A1 promoter activity 6- to 8-fold. Deletion of the EGF response element (EGF-RE) between -92 and -77 bp reduced ras induction by 60%; however, a residual 3-fold induction remained through the proximal -77 bp. Mutation of the EGF-RE AP-1-like sequence in the context of the native promoter reduced CYP11A1 promoter activation by ras 60%. The EGF-RE sequence was sufficient for 6-fold activation by ras in the context of an heterologous thymidine kinase promoter. Candidate transcription factor targets (c-Jun, c-Ets-2) for the ras-signaling cascade were examined for their effects on CYP11A1 promoter activity. Overexpression of c-Jun induced the CYP11A1 promoter through the EGF-RE; however, c-Ets-2 activation of the CYP11A1 promoter (12-fold) required the proximal ras-responsive promoter sequences that are distinct from the EGF/MEK/c-Jun-responsive element. Induction of the CYP11A1 promoter by EGF involves a ras/MEK1/AP-1-dependent pathway that is distinct from induction by ras/c-Ets-2.
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PMID:Stimulation of the P-450 side chain cleavage enzyme (CYP11A1) promoter through ras- and Ets-2-signaling pathways. 888 43

Exposure of mammalian cells to ultraviolet (UV) light or high osmolarity strongly activates the c-Jun amino-terminal protein kinase (JNK) cascade, causing induction of many target genes. Exposure to UV light or osmotic shock induced clustering and internalization of cell surface receptors for epidermal growth factor (EGF), tumor necrosis factor (TNF), and interleukin-1 (IL-1). Activation of the EGF and TNF receptors was also detected biochemically. Whereas activation of each receptor alone resulted in modest activation of JNK, coadministration of EGF, IL-1, and TNF resulted in a strong synergistic response equal to that caused by exposure to osmotic shock or UV light. Inhibition of clustering or receptor down-regulation attenuated both the osmotic shock and UV responses. Physical stresses may perturb the cell surface or alter receptor conformation, thereby subverting signaling pathways normally used by growth factors and cytokines.
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PMID:Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. 889 68


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