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)

Although a novel second form of GnRH (GnRH-II) has been reported to have an antiproliferative effect on gynecologic cancer cells, its biological mechanism remains to be elucidated. We have previously demonstrated that GnRH-II activates p38 MAPK. There is accumulating evidence that activation of MAPKs by GnRH-I and -II is important for cell proliferation, differentiation, and apoptosis. In the present study, we further investigated the involvement of GnRH-II in the inhibition of cell proliferation and activation of ERK1/2 and c-Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) in ovarian cancer cells, OVCAR-3. The [(3)H]thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that treatment with GnRH-II suppresses cell proliferation of ovarian cancer cells. Western blot analysis demonstrated that ERK1/2 was activated by GnRH-II (100 nm). Moreover, PD98059 (10 mum), an inhibitor of a MAPK/ERK kinase, reversed the activation of ERK1/2 induced by GnRH-II. The activation of ERK1/2 by GnRH-II subsequently phosphorylated Elk-1 as a downstream pathway, which was blocked by PD98059. On the other hand, it is not likely that GnRH-II activates the JNK/SAPK pathway. Taken together, these results indicate that the ERK1/2 pathway is involved in the effect of GnRH-II on antiproliferation and may be an important target for ovarian cancer therapy.
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PMID:Extracellular signal-regulated protein kinase, but not c-Jun N-terminal kinase, is activated by type II gonadotropin-releasing hormone involved in the inhibition of ovarian cancer cell proliferation. 1559 81

We characterized the biological function of G-120, glycoprotein isolated from the ethanol extract of the herb, Ulmus davidiana Nakai (UDN). G-120 has anti-tumor activity and significantly inhibited proliferation of MCF-7 cells, as measured by the thymidine uptake assay. In addition, MTT and trypan blue exclusion experiments showed that the G-120-mediated inhibition of DNA synthesis may be due to a cytostatic, rather than a cytotoxic effect. Further studies of DNA analysis and propidium iodide staining revealed that G-120 induces apoptosis in MCF-7 cells. Interestingly, G-120 (100 microg/ml) completely suppressed the binding of NF-kappaB to DNA and increased the cytosolic level of IkappaBalpha which prevented nuclear translocation of NF-kappaB. In addition, G-120 increased the expression of c-Jun, Fra-1, and Fra-2, but did not affect the expression of c-Fos. Collectively, it is believed that G-120 exerts an important role in the induction of apoptosis, suppression of NF-kappaB activation, and induction of c-Jun/Fra-1 or c-Jun/Fra-2 dimerization in MCF-7 cells. Consequently, G-120 could be considered as an anti-cancer agent, although further detailed experiments should be performed.
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PMID:Plant-originated glycoprotein, G-120, inhibits the growth of MCF-7 cells and induces their apoptosis. 1581 76

Pramipexole, a novel non-ergot dopamine (DA) agonist, has been successfully applied to the treatment of Parkinson's disease (PD). Although the specific cause of PD remains unknown, recent studies have provided evidence that oxidative stress plays a role in the parthenogenesis of the disease. In the present study, we examined the effect of pramipexole on hydrogen peroxide (H2O2, 100 microM)-induced PC12 cell death, and the intracellular mechanism of this effect. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay revealed that pretreatment of PC12 cells with pramipexole (1-100 microM) resulted in significant protection against H2O2-induced cell death in a concentration-dependent manner. The protective effect of pramipexole was not affected by pretreatment with the DA receptor antagonists sulpiride, spiperone or domperidone, suggesting that the effect of pramipexole is not mediated by DA receptors. In PC12 cells, pramipexole inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, as well as H2O2-induced cytochrome c release and caspase-3 activation with the resultant apoptosis. It was also observed in PC12 cells that H2O2 stimulated phosphorylation of mitogen-activated protein (MAP) kinases, i.e., extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase. Pramipexole inhibited H2O2-induced JNK and p38 MAP kinase, but not ERK1/2 phosphorylation. Furthermore, in these cells experiments with a fluorescent probe, 2-[6-(4'-amino)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid, revealed that pramipexole, the JNK inhibitor SP600125 and the p38 MAP kinase inhibitor SB203580 inhibited the generation of H2O2-induced reactive oxygen species. Caspase inhibitors Z-DEVD-FMK and Z-IETD-FMK, as well as SP600125 and SB203580, inhibited H2O2-induced PC12 cell death to a similar extent as pramipexole. These results suggest that pramipexole exerts a protective effect against oxidative stress-induced PC12 cell death in part through an inhibition of JNK and p38 MAP kinase.
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PMID:Pramipexole protects against H2O2-induced PC12 cell death. 1636 28

Glomerulosclerosis is a common disorder in many types of chronic kidney diseases. Previous studies have shown that glomerular mesangial cells (MCs) play an important role in the pathogenesis of glomerulosclerosis. The ability of saikosaponin-d (SSd) to reduce the damage of kidney in progressive glomerulosclerosis has been demonstrated. In this study, the effects of saikosaponin-d on MC proliferation and synthesis of extracellular matrix proteins were investigated. Rat MCs were isolated from Wistar rats and cultured in Dulbecco's modified Eagle's medium. MCs were challenged with lipopolysacchorides and incubated with different concentrations of SSd. Cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and lactate dehydrogenase assays. Type IV collagen, fibronectin, and TGF-beta1 in the conditioned medium were measured. The expression of cyclin-dependent kinase 4, c-Jun, and c-Fos was determined by immunohistochemistry. At a concentration of 4 microg/mL or lower, SSd inhibited MC proliferation but did not cause cell death. SSd also inhibited lipopolysaccharide-induced secretion of type IV collagen, fibronectin, and TGF-beta1 in MCs. Additionally, SSd reduced the expression of CDK4, c-Jun, and c-Fos in MCs. We conclude that SSd inhibited MC proliferation and synthesis of extracullular matrix proteins through the downregulation of the CDK4, c-Jun, and c-Fos genes.
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PMID:Mechanism of saikosaponin-d in the regulation of rat mesangial cell proliferation and synthesis of extracellular matrix proteins. 1753 96

The mechanism of acacetin-induced apoptosis of human breast cancer MCF-7 cells was investigated. Acacetin caused 50% growth inhibition (IC50) of MCF-7 cells at 26.4% 0.7% M over 24 h in the MTT assay. Apoptosis was characterized by DNA fragmentation and an increase of sub-G1 cells and involved activation of caspase-7 and PARP (poly-ADP-ribose polymerase). Maximum caspase 7 activity was observed with 100 microM acacetin for 24 h. Caspase 8 and 9 activation cascades mediated the activation of caspase 7. Acacetin caused a reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c and apoptosis inducing factor (AIF) into the cytoplasm, enhancing ROS generation and subsequently resulting in apoptosis. Pretreatment of cells with N-acetylcysteine (NAC) reduced ROS generation and cell growth inhibition, and pretreatment with NAC or a caspase 8 inhibitor (Z-IETD-FMK) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c and AIF. Stress-activated protein kinase/c-Jun NH4-terminal kinase 1/2 (SAPK/ JNK1/2) and c-Jun were activated by acacetin but extracellular-regulated kinase 1/2 (Erk1/2) nor p38 mitogen-activated protein kinase (MAPK) were not. Our results show that acacetin-induced apoptosis of MCF-7 cells is mediated by caspase activation cascades, ROS generation, mitochondria-mediated cell death signaling and the SAPK/JNK1/2-c-Jun signaling pathway, activated by acacetin-induced ROS generation.
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PMID:Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation. 1784 3

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

Oxidative stress induced by reactive oxygen species has been strongly associated with the pathogenesis of neurodegenerative disorders, including Alzheimer's disease. In this study, we investigated the possible protective effects of a cocoa procyanidin fraction (CPF) and procyanidin B2 (epicatechin-(4beta-8)-epicatechin) - a major polyphenol in cocoa - against apoptosis of PC12 rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H(2)O(2)). CPF (1 and 5 microg/ml) and procyanidin B2 (1 and 5 microM) reduced PC12 cell death caused by H(2)O(2), as determined by MTT and trypan blue exclusion assays. CPF and procyanidin B2 attenuated the H(2)O(2)-induced fragmentation of nucleus and DNA in PC12 cells. Western blot data demonstrated that H(2)O(2) induced cleavage of poly(ADP-ribose)polymerase (PARP), downregulated Bcl-X(L) and Bcl-2 in PC12 cells. Pretreatment with CPF or procyanidin B2 before H(2)O(2) treatment diminished PARP cleavage and increased Bcl-X(L) and Bcl-2 expression compared with those only treated with H(2)O(2). Activation of caspase-3 by H(2)O(2) was inhibited by pretreatment with CPF or procyanidin B2. Furthermore, H(2)O(2)-induced rapid and significant phosphorylation of c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and both of these effects were attenuated by CPF or procyanidin B2 treatment. These results suggest that the protective effects of CPF and procyanidin B2 against H(2)O(2)-induced apoptosis involve inhibiting the downregulation of Bcl-X(L) and Bcl-2 expression through blocking the activation of JNK and p38 MAPK.
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PMID:Cocoa procyanidins protect PC12 cells from hydrogen-peroxide-induced apoptosis by inhibiting activation of p38 MAPK and JNK. 1827 86

We investigate the cytotoxic effect of metal protoporphyrins including ferric protoporphyrin (FePP; hemin), cobalt protoporphyrin (CoPP), and tin protoporphyrin (SnPP) in glioblastoma cells C6 and GBM8401. Data of MTT assay show that FePP and CoPP, but not SnPP, significantly reduce the viability of glioma cells C6 and GBM8401 in the absence of serum. In the condition with fetal bovine serum (FBS) or bovine serum albumin (BSA), the cytotoxic effect of FePP and CoPP was completely inhibited. Binding of FePP, CoPP, and SnPP with BSA was examined via spectrophotometer analysis, and the protective effect of serum against FePP and CoPP-induced cell death was abolished by BSA depletion. A loss in the integrity of DNA with an occurrence of apoptotic events including DNA ladders, caspase 3 and PARP protein cleavage, and chromatin-condensed cells is observed in FePP-treated or CoPP-treated C6 cells. An increase in intracellular peroxide level was examined in FePP, but not CoPP, -treated C6 cells, and N-acetyl-l-cysteine (NAC) addition significantly protected C6 cells from FePP, but not CoPP, -induced cell death with reducing FePP-stimulated reactive oxygen species (ROS) production. Activation of extracellular regulated kinases (ERKs) and c-Jun-N-terminal kinases (JNKs) with an increase in the heme oxygenase-1 (HO-1) protein was observed in FePP-treated or CoPP-treated C6 cells in the absence of FBS or BSA, and adding JNKs inhibitor SP600125 (SP), but not ERKs inhibitor PD98059 (PD), significantly attenuated FePP-induced or CoPP-induced HO-1 protein expression in accordance with reducing JNKs protein phosphorylation. However, PD98059, SP600125, or transfection of C6 cells with antisense HO-1 oligonucleotides show no effect on the cytotoxicity elicited by FePP and CoPP in C6 cells. Effect of serum and BSA on the cytotoxicity of metal protoporphyrins in glioma cells is first demonstrated in the present study, and the roles of ROS, MAPKs, and HO-1 were elucidated.
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PMID:Cytotoxic effects of metal protoporphyrins in glioblastoma cells: roles of albumin, reactive oxygen species, and heme oxygenase-1. 1828 2

Transcription factor c-Jun affects neuronal cell death and survival in mammalian brain. As general anesthetics, such as ketamine and propofol, are thought to provide some degree of neuroprotection, this study was intended to test whether the protection of injured neuronal PC12 cells by ketamine and propofol is related to the inhibition of phospho-c-Jun. Using neuronal PC12 cells from rat pheochromocytoma cells differentiated with nerve growth factor, we found that 24 hours of exposure to glutamate (1 to 100 mM) induced concentration-dependent cell death as determined by an ability to reduce the tetrazolium derivative, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) into a blue formazan salt. Neuronal PC12 cells were exposed to ketamine (0.1, 1.0 mM) or propofol (0.5, 5.0 microM) and glutamate (0, 20 mM) for 24 hours. Cell injury was assessed using MTT, in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling, and c-Jun activity assay. Glutamate, 20 mM, induced about 70% of cell death as determined by MTT and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining. Glutamate-induced cell death was related to an increase in expression of phospho-c-Jun. Glutamate-induced cell death was reduced by ketamine (0.1, 1.0 mM) in a dose-dependent manner and also by propofol (0.5, 5.0 microM). In addition, the expression of phospho-c-Jun was substantially reduced by ketamine (0.1, 1.0 mM) and propofol (0.5, 5.0 microM), respectively, as determined by Western blot assay. These results suggest that inhibition of c-Jun activity is involved in the neuroprotective effects of ketamine and propofol on glutamate-induced injury in neuronal PC12 cells.
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PMID:Glutamate-induced c-Jun expression in neuronal PC12 cells: the effects of ketamine and propofol. 1836 74

The developing brain is very sensitive to damage by toxic agents, many of which only manifest in adulthood. Cadmium [Cd(II)] is an environmental pollutant which is widely used in industry and is a constituent of tobacco smoke. Exposure to Cd(II) has been linked to detrimental effects on mammalian cells including neural cells. We have investigated the action of Cd(II) on immature hippocampus by assessing cell viability and modulation of AKT/PKB and mitogen-activated protein kinase (MAPK) family members including extracellular signal-regulated kinase (ERK)-1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). Hippocampal slices from immature rats (postnatal day 14; PN14) were incubated with Cd(II) (5-200 microM) for 3h and the effects on protein phosphorylation were analyzed by western blotting. Phosphorylation of p38(MAPK) was enhanced by Cd(II) at all doses tested. Cd(II) also stimulated the phosphorylation of ERK1/2 in a concentration-dependent manner. However, the phosphorylation of JNK and AKT was not altered by the metal. Moreover, Cd(II) reduced cell viability, as measured by MTT reduction. Inhibition of p38 MAPK by SB203580 aggravated the acute Cd(II)-induced impairment of cell viability, whereas inhibition of MEK by PD98059 did not alter the effects of Cd(II). The present data suggest that in immature hippocampal cells p38 MAPK may be a part of signaling pathway that counteracts acute Cd(II) neurotoxicity. In conclusion, our results showed that Cd(II) impairs cell viability and disturbs MAPKs pathways in an important developmental stage for synaptic organization.
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PMID:Neurotoxicity of cadmium on immature hippocampus and a neuroprotective role for p38 MAPK. 1854 2


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