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)

A dimer of the basic region leucine zipper proteins c-Jun and c-Fos constitutes the classical activator protein-1 (AP-1) transcription factor. c-Jun is thought to play essential roles in many important cellular pathways, including the control of proliferation and cell death. To investigate the roles of c-Jun and c-Fos concentrations in the regulation of neuronal cell death, we generated conditional alleles by fusing c-Jun and c-Fos to the ligand binding domain of the murine estrogen receptor (ER), with the aim of controlling the biological activities of c-Jun and c-Fos by the synthetic ligand 4-hydroxytamoxifen (4OHT). Transient transfection experiments revealed an increase in AP-1 activity following transfection of an expression vector encoding a c-Jun/estrogen receptor fusion protein (c-JunER) and stimulation with 4OHT. In contrast, a c-Fos/estrogen receptor fusion protein (c-FosER) was only weakly active in HT22 immortalized hippocampal cells and in PC12 pheochromocytoma cells. Highest levels of AP-1 activity were obtained by cotransfection of c-FosER and c-JunER and stimulation with 4OHT. Using retroviral gene transfer, we generated HT22 and PC12 cells expressing either c-JunER or c-FosER. The AP-1 activity was moderately increased in 4OHT-treated HT22 and PC12 cells expressing c-JunER, whereas no biological activity was observed in cells expressing c-FosER. We tested the influence of 4OHT-activated c-JunER or c-FosER upon cell survival and cell death by quantification of mitochondrial reduction capacity of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to formazan dye crystals. We did not observe any 4OHT-dependent decrease in cell survival in cells expressing c-JunER or c-FosER. Likewise, the number of pycnic nuclei did not increase in HT22 or PC12 cells expressing c-JunER or c-FosER. We conclude that an increase in the c-Jun concentration is not sufficient to trigger neuronal cell death. We propose that it is not the concentration of c-Jun that is critical for cell survival but rather the concentration of active, i.e., phosphorylated c-Jun.
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PMID:Role of c-Jun concentration in neuronal cell death. 1242 33

Low-level exposure of manganese (Mn2+) induces adverse neurological effects. We have previously shown that low-level Mn2+ exposure induces cell death in dopaminergic neurons, in which the redox-sensitive transcription factor nuclear factor kappa-B (NF-kappaB) and associated mitogen-activated protein kinase (MAPK) were stimulated. In continuation of this work, we evaluated the activator protein-1 (AP-1). DNA binding activity and N-terminal c-Jun kinase (JNK) activation due to low-level exposure to manganese. Rat catecholaminergic-rich pheochromocytoma (PC12) cells were exposed to low concentrations of Mn2+ (0-10 microM) for 120 min and examined changes in AP-1 DNA binding activity by electrophoretic mobility shift assay (EMSA). Mn(2+)-exposed cells produced a eightfold increase in AP-1 DNA binding activity compared to untreated controls. This significant increase was seen within 60 min after Mn2+ exposure. In addition, Mn2+ activated N-terminal c-Jun kinase, suggesting that the JNK pathway is involved in Mn(2+)-induced AP-1 activation. Thus, JNK activation may in turn stimulate AP-1 via c-Jun phosphorylation. Since the transcription factors NF-kappaB and AP-1 have been shown to play an essential role in oxidative stress related toxicity, we suggest that induction of the signaling factor AP-1 during Mn2+ exposure in the present study may have a significant cytotoxic effect on neuronal function.
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PMID:Activation of activator protein-1 DNA binding activity due to low level manganese exposure in pheochromocytoma cells. 1510 15

We investigated the cell death effects of eight xanthones on PC12 rat pheochromocytoma cells. Among these compounds, alpha-mangostin, from the fruit hull of Garcinia mangostana L., had the most potent effect with the EC(50) value of 4 microM. Alpha-mangostin-treated PC12 cells demonstrated typical apoptotic DNA fragmentation and caspase-3 cleavage (equivalent to activation). The flow cytometric analysis indicated that this compound induced apoptosis in time-and concentration-dependent manners. Alpha-mangostin showed the features of the mitochondrial apoptotic pathway such as mitochondrial membrane depolarization and cytochrome c release. Furthermore, alpha-mangostin inhibited the sarco(endo)plasmic reticulum Ca(2+)-ATPase markedly. There was a correlation between the Ca(2+)-ATPase inhibitory effects and the apoptotic effects of the xanthone derivatives. On the other hand, c-Jun NH(2)-terminal kinase (JNK/SAPK), one of the signaling molecules of endoplasmic reticulum (ER) stress, was activated with alpha-mangostin treatment. These results suggest that alpha-mangostin inhibits Ca(2+)-ATPase to cause apoptosis through the mitochondrial pathway.
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PMID:Alpha-mangostin induces Ca2+-ATPase-dependent apoptosis via mitochondrial pathway in PC12 cells. 1515 48

Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EglN3 acts downstream of c-Jun and is specifically required among the three EglN family members for apoptosis in this setting. Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.
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PMID:Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. 1609 60

1. Colostrinin (CLN) induces maturation and differentiation of murine thymocytes, promotes proliferation of peripheral blood leukocytes, induces immunomodulator cytokines, and ameliorates oxidative stress-mediated activation of c-Jun NH2-terminal kinases. 2. Here we report that upon treatment with CLN, medullary pheochromocytoma (PC12) cells ceased to proliferate and extend neurites. 3. The arrest of CLN-treated PC12 cells in the G1 phase of the cell cycle was due to an increase in the phosphorylation of p53 at serine(15) (p53ser15) and expression of p21WAF1. PC12 cells treated with inhibitory oligonucleotides to p53 lacked p53ser15 and p21WAF1 expression, and did not show morphological changes after CLN exposure. Transfection with inhibitory oligonucleotides to p21WAF1 had no effect on p53 activation; however, cells failed to arrest or extend neurites. An oligonucleotide inhibiting luciferase expression had no effect on CLN-mediated p53 activation, p21WAF1 expression, growth arrest, or neurite outgrowth. 4. We conclude that CLN induces delicate cassettes of signaling pathways common to cell proliferation and differentiation, and mediates activities that are similar to those of hormones and neurotrophins, leading to neurite outgrowth.
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PMID:Colostrinin-driven neurite outgrowth requires p53 activation in PC12 cells. 1639 41

Astrocytes are thought to be critical to neurons' surviving damage caused by ischemic stroke or other injury. Plasminogen activator inhibitor-1 is one of the active soluble factors released by astrocytes and regulates plasminogen activator-plasmin proteolytic sequence in the CNS as a serpin. In this study, we show that plasminogen activator inhibitor-1 can promote neurite outgrowth and survival of rat pheochromocytoma cells in serum-deprived conditions, and that this neuroprotective activity is correlated with enhanced activation of both extracellular signal-regulated kinases following a direct phosphorylation of nerve growth factor receptor, Trk A, and of c-Jun. Our results suggest that plasminogen activator inhibitor-1 can act as a neurotrophic factor, protecting neurons from serum deprivation-induced neuron death not only by compensating for nerve growth factor functions, but also by activating the c-Jun/activating protein-1 pathway.
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PMID:Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extracellular signal-regulated kinase and c-Jun pathways. 1667 72

Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a common event in hereditary (von Hippel- Lindau disease) and sporadic hemangioblastomas and clear-cell renal carcinomas. Germ-line VHL mutations are also linked to some hereditary pheochromocytoma families. The VHL gene product, pVHL, interacts with a number of cellular proteins and is implicated in the control of angiogenesis, extracellular matrix formation, cell metabolism, and mitogenesis. The best understood function of pVHL relates to its role as the substrate recognition unit of an E3 ligase that targets the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction in the presence of oxygen. Down-regulation of HIF appears to be both necessary and sufficient for renal tumor suppression by pVHL, and HIF is strongly suspected of contributing to hemangioblastoma development as well. Recent work suggests that pVHL's role in pheochromocytoma is not related to HIF but rather to the ability of pVHL to regulate neuronal apoptosis, which is mediated by c-Jun, when growth factors such as NGF become limiting. Loss of pVHL leads to up-regulation of JunB, which antagonizes c-Jun and blunts apoptosis.
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PMID:The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing. 1686 49

Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the substantia nigra of the brain. Although the underlying causes are not well characterized, epidemiological studies suggest an elevated risk of PD with occupational pesticide exposure. Here, we utilized pheochromocytoma (PC) 12 and SH-SY5Y cells as well as rat primary cultured dopaminergic neurons to investigate mechanisms for dopaminergic cell death induced by paraquat and rotenone, pesticides that are used to model PD in rodents. Both paraquat and rotenone induce selective loss of dopaminergic neurons in primary cultures. We discovered that paraquat induces apoptosis in PC12 cells but not in SH-SY5Y cells, while rotenone exposure causes apoptosis in SH-SY5Y cells but not in PC12 cells. The selective ability of paraquat and rotenone to induce apoptosis in different cell lines correlates with their ability to activate c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinases. Furthermore, JNK and p38 are required for rotenone-induced apoptosis in SH-SY5Y cells (K. Newhouse et al., 2004, Toxicol. Sci. 79, 137-146) as well as primary neurons, and for paraquat-induced apoptosis in PC12 cells. However, JNK but not p38 plays a role in paraquat-induced loss of primary cultured dopaminergic neurons. Our data identify JNK activation as a common mechanism underlying dopaminergic cell death induced by both paraquat and rotenone in model cell lines and primary cultures.
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PMID:Activation of c-Jun N-terminal protein kinase is a common mechanism underlying paraquat- and rotenone-induced dopaminergic cell apoptosis. 1732 51

There is mounting evidence implicating the accumulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease. Recently, considerable attention has been focused on identifying naturally occurring antioxidants that are able to reduce excess ROS and RNS, thereby protecting against oxidative stress and neuron death. The present study investigated the possible protective effects of piceatannol (trans-3,4,3',5'-tetrahydroxystilbene), which is present in grapes and other foods, on hydrogen-peroxide- and peroxynitrite-induced oxidative cell death. PC12 rat pheochromocytoma (PC12) cells treated with hydrogen peroxide or SIN-1 (a peroxynitrite-generating compound) exhibited apoptotic death, as determined by nucleus condensation and cleavage of poly(ADP-ribose)polymerase (PARP). Piceatannol treatment attenuated hydrogen-peroxide- and peroxynitrite-induced cytotoxicity, apoptotic features, PARP cleavage and intracellular ROS and RNS accumulation. Treatment of PC12 cells with hydrogen peroxide or SIN-1 led to down-regulation of Bcl-X(L) and activation of caspase-3 and -8, which were also inhibited by piceatannol treatment. Hydrogen peroxide or SIN-1 treatment induced phosphorylation of the c-Jun-N-terminal kinase (JNK), which was inhibited by piceatannol treatment. Moreover, SP600125 (a JNK inhibitor) significantly inhibited hydrogen-peroxide- and peroxynitrite-induced PC12 cell death, revealing inactivation of the JNK pathway as a possible molecular mechanism for the protective effects of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells. Collectively, these findings suggest that the protective effect of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells is associated with blocking the activation of JNK and the down-regulation of Bcl-XL.
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PMID:Piceatannol attenuates hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells by blocking down-regulation of Bcl-XL and activation of JNK. 1786 87

Antrodia cinnamomea (formerly A. camphorata) has recently and commercially been used in the formulation of nutraceuticals and functional foods in Taiwan. Because of its diverse properties, the neuroprotective effect was investigated using a fermented A. cinnamomea extract in this study. Serum deprivation-induced apoptosis in neuronal-like pheochromocytoma (PC12) cells was used as a cell stress model, and it was found that A. cinnamomea was effective in preventing serum-deprived apoptosis according to results of an MTT assay and Hoechst staining. Serum deprivation resulted in decreased phosphorylation of extracellular signal-regulated kinase (ERK) and increased phosphorylations of c-Jun NH2-terminal kinase (JNK) and p38, of the family of mitogen-activated protein kinases (MAPKs); however, A. cinnamomea reversed these phenomena, supporting the antagonistic effects between ERK and JNK-p38 in regulating cell survival. The previously identified active component of A. cinnamomea, adenosine (ADO), also exerted the same effects as A. cinnamomea in preventing apoptosis and regulating phosphorylations of MAPKs. Although an inhibitor of the ERK upstream activator blocked A. cinnamomea-induced ERK phosphorylations, it failed to block the protection of A. cinnamomea and ADO. A protein kinase A (PKA) inhibitor blocked the protection by both A. cinnamomea and ADO. Both JNK and p38 inhibitors were effective in preventing the phosphorylations of JNK and p38 and serum deprivation-induced apoptosis. Collectively, A. cinnamomea prevented serum deprivation-induced PC12 cell apoptosis through a PKA-dependent pathway and by suppression of JNK and p38 activities.
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PMID:Fermented Antrodia cinnamomea extract protects rat PC12 cells from serum deprivation-induced apoptosis: the role of the MAPK family. 1818 5


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