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)

12-O-Tetradecanoylphorbol-13-acetate (TPA) is widely used as a tumor promoter with organotropy in skin and esophagus. TPA-induced, organ-specific tumor promotion is not correlated with the distribution of its receptor, protein kinase C (PKC). Using five administration methods (painting, drinking, gavage feeding, i.p. injection, and i.v. injection), we analyzed TPA-stimulated activator protein-1 (AP-1) activity in various organs (liver, kidney, brain, lung, spleen, heart, stomach, colon, esophagus, and skin) from transgenic mice expressing the AP-1 luciferase reporter gene. Topical application of TPA by painting the skin on the back of mice raised AP-1 activity 122.6-fold, and the highest peak of AP-1 activity was at 12 h after administration of TPA. Drinking water containing TPA caused a 25.8-fold induction of AP-1 activity in the skin, whereas gavage feeding with TPA caused a 34.2-fold induction of AP-1 in the skin. Intraperitoneal or i.v. injection of TPA induced a 49.56-fold or 20.4-fold increase in AP-1 activity in the skin, respectively. The highest peaks of AP-1 activity in the skin were at 12 h after drinking, feeding, or injection of TPA. More interesting, in the esophagus, i.p. injection of TPA raised AP-1 activity 13.9-fold, drinking TPA raised AP-1 activity 8.4-fold, and painting with TPA caused a 2.4-fold induction of AP-1 activity. In the colon, i.p. injection of TPA raised AP-1 activity 3.9-fold, drinking TPA induced a 1.2-fold increase in AP-1 activity, but painting with TPA had no effect. AP-1 activity in other organs was not detectable after administration of TPA by painting, drinking, or injection. Phosphorylation of extracellular signal-regulated kinases in the skin increased at 12 h after painting, drinking, or i.p. injection of TPA. In addition, phosphorylation of p38 kinase was raised slightly after TPA administration, but phosphorylation of c-Jun NH(2)-terminal kinases was not detected at any time point after TPA administration. Similar changes in MAP kinases were also seen in the esophagus after TPA administration. These results indicate that the skin is the most sensitive organ to TPA induction of AP-1 activity. The data suggest that the organ-specific, tumor-promoting effect of TPA may be through AP-1 activation and phosphorylation of ERKs and p38 kinase.
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PMID:Organ-specific activation of activator protein-1 in transgenic mice by 12-o-tetradecanoylphorbol-13-acetate with different administration methods. 1135 30

p38 MAP kinases (p38) and c-Jun N-terminal protein kinases (JNK) have been associated with TNF-alpha-induced apoptosis. However, recent studies indicate that an early but brief activation of JNK and/or p38 may actually protect some cells from TNF-alpha-induced apoptosis. Whether the activation of JNK and p38 provides a pro- or anti-apoptotic signal for TNF-alpha has been controversial. In this study, we investigated the role of p38 in the regulation of TNF-alpha cytotoxicity in rat mesangial cells. Treatment of the cells with TNF-alpha alone had little effect on their viability, but they became very sensitive to apoptosis when treated with TNF-alpha in the presence of the p38 inhibitor SB 203580. These results suggested that the p38 pathway is critical for mesangial cells to survive the toxic effect of TNF-alpha. Using adenovirus-mediated gene transfer technique, we further demonstrated that p38beta, but not p38alpha, is essential to protect the cells from TNF-alpha toxicity. It has been speculated that there is a synergetic interaction between the p38 and the nuclear factor-kappaB (NF-kappaB) pathways in protecting certain cells from apoptosis. However, expression of neither p38beta nor its dominant negative mutant in mesangial cells interfered with TNF-alpha-induced translocation of NF-kappaB, the initial step of NF-kappaB activation. While it is unclear whether p38beta regulates NF-kappaB transcription activity at other steps, it is apparent that p38beta does not affect TNF-alpha-induced NF-kappaB activation at the stage of nuclear translocation.
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PMID:p38beta MAP kinase protects rat mesangial cells from TNF-alpha-induced apoptosis. 1150 Sep 33

The c-Jun N-terminal kinase (JNK) signal transduction pathway is activated in response to the exposure of cells to environmental stress. Components of the JNK signaling pathway interact with the JIP1 scaffold protein. JIP1 is located in the neurites of primary hippocampal neurons. However, in response to stress, JIP1 accumulates in the soma together with activated JNK and phosphorylated c-Jun. Disruption of the Jip1 gene in mice by homologous recombination prevented JNK activation caused by exposure to excitotoxic stress and anoxic stress in vivo and in vitro. These data show that the JIP1 scaffold protein is a critical component of a MAP-kinase signal transduction pathway.
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PMID:Requirement of the JIP1 scaffold protein for stress-induced JNK activation. 1156 51

Release of nitric oxide (NO) during inflammation can induce apoptosis in the heart. Here we analyzed the involvement of members of the mitogen-activated protein kinase (MAPK) family and their downstream target, the transcription factor AP-1, in induction of apoptosis by NO in isolated adult cardiomyocytes of rat. The NO-donor (+/-)-S-nitroso-N-acetylpenicillamine (100 microM SNAP)-induced apoptosis in 10.5 +/- 0.7% of cardiomyocytes and activated the transcription activator protein AP-1 by 333.6 +/- 122.3%. Intracellular scavenging of AP-1 with decoy-oligonucleotides blocked NO-induced apoptosis to control levels (3.8 +/- 0.5% apoptotic cells). Activation of AP-1 with a c-Jun amino-terminal kinase (JNK) activator (Ro318220, 10 microM) provoked apoptosis in 18.7 +/- 1.2% cardiomyocytes, which was again blocked by intracellular scavenging of AP-1. NO activated JNK by 87.0 +/- 27.3% and extracellular signal-regulated kinase (ERK) by 35 +/- 3%. Inhibition of ERK by the mitogen-activated protein kinase kinase (MEK1) inhibitor PD98059 (10 microM) abolished AP-1 activation and apoptosis induction with SNAP. Evidence that p38 MAPK plays a role in NO-induced apoptosis was not found. These results clearly demonstrate the involvement of the transcription factor AP-1 in NO-induced apoptosis in cardiomyocytes. The activation of AP-1 is mediated by the two MAP kinases JNK and ERK.
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PMID:Transcription activator protein 1 (AP-1) mediates NO-induced apoptosis of adult cardiomyocytes. 1164 Dec 66

Protection against ischemic kidney injury is afforded by 24 h of ureteral obstruction (UO) applied 6 or 8 days prior to the ischemia. Uremia or humoral factors are not responsible for the protection, since unilateral UO confers protection on that kidney but not the contralateral kidney. Prior UO results in reduced postischemic outer medullary congestion and leukocyte infiltration. Prior UO results in reduced postischemic phosphorylation of c-Jun N-terminal stress-activated protein kinase 1/2 (JNK1/2), p38, mitogen-activated protein kinase (MAPK) kinase 4 (MKK4), and MKK3/6. Very few cells stain positively for proliferating cell nuclear antigen after obstruction, indicating that subsequent protection against ischemia is not related to proliferation with increased numbers of newly formed daughter cells more resistant to injury. UO increases the expression of heat shock protein (HSP)-25 and HSP-72. The increased HSP-25 expression persists for 6 or 8 days, whereas HSP-72 does not. HSP-25 expression is increased in the proximal tubule cells in the outer stripe of the outer medulla postobstruction, prior to, and 24 h after ischemia. In LLC-PK(1) renal epithelial cells, adenovirus-expressed human HSP-27 confers resistance to chemical anoxia and oxidative stress. Increased HSP-27 expression in LLC-PK(1) cells results in reduced H(2)O(2)-induced phosphorylation of JNK1/2 and p38. In conclusion, prior transient UO renders the kidney resistant to ischemia. This resistance to functional consequences of ischemia is associated with reduced postischemic activation of JNK, p38 MAP kinases, and their upstream MAPK kinases. The persistent increase in HSP-25 that occurs as a result of UO may contribute to the reduction in phosphorylation of MAPKs that have been implicated in adhesion molecule up-regulation and cell death.
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PMID:Prevention of kidney ischemia/reperfusion-induced functional injury, MAPK and MAPK kinase activation, and inflammation by remote transient ureteral obstruction. 1169 40

Proteins of Ras family play an important role in regulation of cell growth and proliferation, and their mutations can lead to growth factor-independent proliferation due to constitutive activity of various signal transduction cascades. In the present work, we studied the activity of ERK, JNK and p38 MAP-kinase cascades in rat embryo fibroblast cells transformed with oncogenes E1A and cHa-ras. These transformed cells are characterized by a high and non-regulated activity of transcription factor AP-1 involved in the regulation of cell proliferation. Since phosphorylation of AP-1 depends on the activity of relevant MAP-kinase cascades (ERK, JNK and p38), we analysed the expression of non-phosphorylated forms of the kinases and their phosphorylated state in E1A + cHa-ras cells using antibodies specific to non-phosphorylated and phosphorylated proteins. It has been established that transformed cells contain higher amounts of non-phosphorylated ERK, JNK and p38 kinases, thus implying a reduced degradation of these and other proteins in the transformants. The content of phosphorylated (active) forms studied in Western blot-analysis with phosphoantibodies was shown to be also higher in exponentially growing E1A + cHa-ras cells. But serum stimulation of the starved cells gave insignificant rise to an increase of ERK, JNK and p38 phosphorylation. Nevertheless, an in vitro kinase assay performed with the kinases, either immunoprecipitated by antibody or bound to GST-fusion substrates, enabled us to show a certain level of stimulation of c-Jun-associated (JNK) and MEF2A-associated (p38) kinase activity in serum stimulated E1A + cHa-ras cells. Thus, the obtained results show that transformation of fibroblasts with E1A and ras oncogenes may contribute to constitutive activation of ERK, JNK and p38 kinase cascades responsible for a high and non-regulated activity of MAP-kinase-dependent transcription factors, in particular AP-1.
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PMID:[Constitutive activity of MAP kinase cascades in REF cells transformed by E1A and cHa-ras oncogenes]. 1176 29

High concentrations of non steroidal antiinflammatory drugs (NSAIDs) exert preventive effects against carcinogenesis. Their molecular mechanism of action remains to be elucidated. Based on previous reports with salicylate, we have made the hypothesis that various NSAIDs can activate the mitogen-activated protein kinases (MAPK). Moreover, we tested the idea that NSAIDs act by increasing the effects of oxidative stress. We report that in human colorectal carcinoma cells NSAIDs stimulated the three families of MAPK, extracellular regulated kinases, c-Jun N-terminal kinases, p38 MAPK and that this stimulation is prevented by N-acetyl cysteine. In cultured astrocytes, a biological system less sensitive to oxidative stress, we show that a short treatment by NSAIDs strongly activated the three MAP kinases in the presence of H(2)O(2). A 25 microM H(2)O(2), unable to stimulate by itself the MAP kinases, promote an almost complete activation of MAP kinases in the presence of NSAIDs. The activation of MAP kinases by H(2)O(2) and NSAIDs was suppressed by quinone reductase inhibitors, suggesting that "redox cycling" was involved in the activation mechanisms of MAP kinases by H(2)O(2) and NSAIDs. The mobility on SDS-PAGE of the apoptosis signal-regulating kinase, which activates C-Jun N-terminal kinases and p38 MAPK cascades, was reduced by H(2)O(2) and NSAIDs, suggesting, that H(2)O(2) and NSAIDs activated apoptosis signal-regulating kinase by increasing its state of phosphorylation. In conclusion, we demonstrate that various NSAIDs can activate the three families of MAP kinases and that this activation depends on the presence of reactive oxygenated species. These results give a new insight into the mechanism of the action of NSAIDs.
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PMID:Role of redox status on the activation of mitogen-activated protein kinase cascades by NSAIDs. 1184 90

Over the past few years we have studied the plasticity of the adult auditory brainstem in the rat following unilateral changes to the pattern of sensory activation, either by intracochlear electrical stimulation or by deafening. We discovered that modifications to afferent activity induced changes in the molecular composition and cellular morphology throughout the auditory brainstem, including its major centers: the cochlear nucleus complex, the superior olivary complex, and the inferior colliculus. The time window studied ranged from 2 h to over 1 year following induction of changes to afferent activity. The molecular markers employed include the NMDA receptor subunit type 1, the cAMP response element binding protein (CREB), the immediate early gene products c-Fos, c-Jun and Egr-1, the growth and plasticity-associated protein GAP-43 and its mRNA, the calcium binding protein calbindin, the cell adhesion molecule integrin-alpha(1), the microtubule-associated protein MAP-1b, and the neurofilament light chain (NF-L). As a consequence of the specific electrical stimulation of the auditory afferents or the loss of hearing, a cascade of events is triggered that apparently modifies the integrative action and computational abilities of the central auditory system. An attempt is made to relate the diverse phenomena observed to a common molecular signaling network that is suspected to bridge sensory experience to changes in the structure and function of the brain. Eventually, a thorough understanding of these events will be essential for the specific diagnosis of patients, optimal timing for implantation, and suitable parameters for running of a cochlear implant or an auditory brainstem implant in humans. In this report an overview of the results obtained in the past years in our lab is presented, flanked by an introduction into the history of plasticity research and a model proposed for intracellular signal cascades related to activity-dependent plasticity.
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PMID:Activity-dependent plasticity in the adult auditory brainstem. 1184 62

We previously showed that cepharanthine (CEP), a biscoclaurine alkaloid, induces caspase-dependent and Fas-independent apoptosis in Jurkat and K562 human leukemia cells. In the present study, we investigated the effect of CEP on three groups of human mitogen-activated protein kinases (MAPKs) in relation to CEP-induced apoptosis. CEP, at the concentration required for and at the time of induction of apoptosis, activated MAPKs p38 in both Jurkat and K562 cells and activated extracellular signal-regulated kinases (ERKs) only in K562 cells. However, CEP treatment did not trigger c-Jun NH(2)-terminal kinases (JNKs) activation. CEP increased the expression and phosphorylation levels of c-Jun and ATF-2 transcription factors. zVAD-fmk, a general caspase inhibitor, did not inhibit CEP-triggered p38 activation in Jurkat and K562 cells or ERK activation in K562 cells. Unexpectedly, pretreatment with a specific p38 inhibitor, SB203580, promoted CEP-induced apoptosis and caspase activation in Jurkat and K562 cells, whereas pretreatment with an MEK-1 inhibitor PD98059 inhibited CEP-induced apoptosis and caspase activation in K562 cells. A selective tyrosine kinase inhibitor, herbimycin A, which completely inhibited CEP-triggered ERKs activation, clearly promoted CEP-induced c-Jun expression and phosphorylation. Our results suggest that each of the three groups of MAP family members is uniquely involved in the CEP-mediated signal cascades in two different leukemia cell lines for inducing/regulating caspase activation and DNA fragmentation.
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PMID:Modes of activation of mitogen-activated protein kinases and their roles in cepharanthine-induced apoptosis in human leukemia cells. 1189 91

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active, phosphorylation-dependent specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, has been examined following systemic administration of kainic acid (KA) at convulsant doses to rats. Increased phosphorylated MAPK (MAPK(P)) immunoreactivity has been found at 3 and 6 h in the vulnerable regions entorhinal cortex and CA3, in which neurons are committed to die, as well as in sensitive regions dentate gyrus and gyrus cinguli, in which neurons will survive. JNK(P) has been observed in the entorhinal cortex and dentate gyrus, and p38(P) immunoreactivity occurs in the entorhinal cortex. Strong c-Myc(P) expression parallels MAPK(P) immunoreactivity in the entorhinal cortex, CA3, dentate gyrus and gyrus cinguli, showing that enhanced c-Myc(P) expression does not preclude cell death or cell survival. Selective decrease of CREB(P) immunoreactivity in entorhinal cortex and CA3 indicates CREB(P) reduction associated with cell death. Strong c-Jun(P) immunoreactivity has been found in the entorhinal cortex, CA3 and dentate gyrus, thus suggesting that regulation of two opposing cellular programs (cell death or cell survival) of c-Jun(P) depends on c-Jun interactions with other factors. Interestingly, ATF-2(P), and to a lesser extent Elk-1(P), is selectively increased in the dentate gyrus. These results suggest ATF-2(P) involvement in cell survival of dentate gyrus granule cells. The present results demonstrate activation of specific MAPK pathways in association with either cell death or cell survival triggered by KA. Furthermore, increased Ras activation, as seen with p21 Ras activation assay, indicates a crucial role for Ras in activating MAP kinases following excitotoxic insult.
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PMID:Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat. 1190 60


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