Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously characterized the cytotoxic action of diallyl disulfide (DADS) on neuroblastoma cells, and we have shown the crucial role of an early and massive reactive oxygen species production in the induction of c-Jun NH(2)-terminal kinase-mediated apoptotic pathway. In the present work, we report that DADS is ineffective in inducing apoptosis in a human adenocarcinoma gastric cell line (AGS). In particular, we show that AGS cells are able to recover from the p53/p21-mediated cell cycle arrest in the G(2)-M phase upon DADS treatment without committing cells to death. This event is most likely due to a peculiar surviving pathway of these cells involving: (a) the formation of mixed disulfides between reduced glutathione (GSH) and protein thiols, (b) a higher and inducible glutathione peroxidase activity, and/or (c) an efficient modulation of the phospho-active levels of the extracellular signal-regulated kinases 1 and 2 (ERK 1/2). Moreover, by increasing glutathione peroxidase expression or GSH concentrations, cell cycle arrest is fully abolished; the apoptotic death is induced by either decreasing the availability of intracellular GSH or inhibiting the reactivation of ERK 1/2. Altogether, our data show that ERK 1/2 participates in the active proliferation of AGS cells and that an efficient reactive oxygen species buffering system makes these cells resistant to DADS-mediated detrimental effects.
 ...
PMID:Glutathione-related systems and modulation of extracellular signal-regulated kinases are involved in the resistance of AGS adenocarcinoma gastric cells to diallyl disulfide-induced apoptosis. 1635 86

Garlic extracts, either aqueous or oily, are commonly employed to prepare garlic derivative supplements used as nutraceuticals for the treatment of different pathologies. In this study, we investigated the effects of water garlic extracts from two different areas of Italy well known for garlic production, Latina (GEL) and Sulmona (GES), on cell cycle and death of HepG2 hepatoma cells. The effects of the treatments with GEL and GES were also compared with the oil-soluble sulfur compound of garlic, diallyl disulfide (DADS). GEL and GES induced a p53/p21-dependent cell cycle arrest in G2/M phase and apoptosis, although to a different extent, whereas DADS, under the experimental conditions used, was not detrimental to HepG2 cells. GEL and GES committed HepG2 cells to apoptosis by the activation of c-Jun-NH(2) terminal kinase (JNK)/c-Jun phosphorylative cascade without a detectable increase in the flux of reactive oxygen species. Moreover, differentiation of HepG2 cells induced by retinoic acid determined resistance to GEL and GES treatments without the activation of JNK signaling pathway. Overall, the results obtained indicate that water-soluble garlic extracts are more inhibitory of the growth of transformed hepatoma cells than the oil-soluble isolated compound DADS, and that their antiproliferative properties are different depending on the area of origin of the starting material.
 ...
PMID:Effects of water garlic extracts on cell cycle and viability of HepG2 hepatoma cells. 1652 31

This study first investigates the anticancer effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) in human nonsmall cell lung cancer cells, A549. Plumbagin has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21 and reduced amounts of cyclinB1, Cdc2, and Cdc25C. Plumbagin treatment also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. Blockade of p53 activity by dominant-negative p53 transfection partially decreased plumbagin-induced apoptosis and G2/M arrest, suggesting it might be operated by p53-dependent and independent pathway. Plumbagin treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that c-Jun NH2-terminal kinase (JNK) is a critical mediator in plumbagin-induced cell growth inhibition. Activation of JNK by plumbagin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and MDM2 interaction. SP600125 (anthra [1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone), a specific inhibitor of JNK, significantly decreased apoptosis by inhibiting the phosphorylation of p53 (serine 15) and subsequently increased the interaction of p53 and MDM2. SP6000125 also inhibited the phosphorylation of Bcl-2 (Ser70) induced by plumbagin. Further investigation revealed that plumbagin's inhibition of cell growth effect was also evident in a nude mice model. Taken together, these results suggest a critical role for JNK and p53 in plumbagin-induced G2/M arrest and apoptosis of human nonsmall cell lung cancer cells.
 ...
PMID:Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c-Jun NH2-terminal kinase-mediated phosphorylation at serine 15 in vitro and in vivo. 1663 41

Epidemiologic evidence suggests that high dietary intake of Brassica vegetables, such as broccoli, cabbage, and Brussels sprouts, protects against tumorigenesis in multiple organs. 3,3'-Diindolylmethane, one of the active products derived from Brassica vegetables, is a promising antitumor agent. Previous studies in our laboratory showed that 3,3'-diindolylmethane induced a G(1) cell cycle arrest in human breast cancer MCF-7 cells by a mechanism that included increased expression of p21. In the present study, the upstream events leading to p21 overexpression were further investigated. We show for the first time that 3,3'-diindolylmethane is a strong mitochondrial H(+)-ATPase inhibitor (IC(50) approximately 20 micromol/L). 3,3'-Diindolylmethane treatment induced hyperpolarization of mitochondrial inner membrane, decreased cellular ATP level, and significantly stimulated mitochondrial reactive oxygen species (ROS) production. ROS production, in turn, led to the activation of stress-activated pathways involving p38 and c-Jun NH(2)-terminal kinase. Using specific kinase inhibitors (SB203580 and SP600125), we showed the central role of p38 and c-Jun NH(2)-terminal kinase (JNK) pathways in 3,3'-diindolylmethane-induced p21 mRNA transcription. In addition, antioxidants significantly attenuated 3,3'-diindolylmethane-induced activation of p38 and JNK and induction of p21, indicating that oxidative stress is the major trigger of these events. To further support the role of ROS in 3,3'-diindolylmethane-induced p21 overexpression, we showed that 3,3'-diindolylmethane failed to induce p21 overexpression in mitochondrial respiratory chain deficient rho(0) MCF-7 cells, in which 3,3'-diindolylmethane did not stimulate ROS production. Thus, we have established the critical role of enhanced mitochondrial ROS release in 3,3'-diindolylmethane-induced p21 up-regulation in human breast cancer cells.
 ...
PMID:3,3'-Diindolylmethane is a novel mitochondrial H(+)-ATP synthase inhibitor that can induce p21(Cip1/Waf1) expression by induction of oxidative stress in human breast cancer cells. 1665 44

To investigate the effects of arsenite on cell proliferation and the signal transduction in hapatocytes in vivo, rats received a single injection of sodium arsenite immediately after partial hepatectomy. Characteristic DNA fragmentation was observed at 4h after the arsenite-injection in partially hepatectomized liver, while it was not detected either in the control (partial hepatectomy only) or arsenite-injected normal (without partial hepatectomy) liver. The effect of the arsenite-injection on the activation of extracellular signal-regulated kinase (ERK) was not observed in the normal or the partially hepatectomized liver. The activity of p38 mitogen-activated protein kinase (MAPK) markedly increased after 15min to 2h after the arsenite-injection in partially hepatectomized liver while no or a less increase was observed in the arsenite-injected normal or the control, respectively. The Jun N-terminal kinase (JNK) was activated to a maximal level, about six-fold the maximum of the control, at 15min after the injection with partial hepatectomy. The arsenite-injection markedly increased the phosphorylated forms of c-Jun and ATF-2 and the protein levels of c-Jun, p53 and p21(WAF1/CIP1) in the partially hepatectomized liver. These results suggested that arsenite induced apoptosis in the hepatocytes in vivo, through the enhancement of the activation of JNK and p38 MAPK caused by partial hepatectomy and the p53-dependent p21(WAF1/CIP1) protein expression.
 ...
PMID:Arsenite induces apoptosis in hepatocytes through an enhancement of the activation of Jun N-terminal kinase and p38 mitogen-activated protein kinase caused by partial hepatectomy. 1679 87

The AP-1 transcription factor c-Jun is a key regulator of hepatocyte proliferation. Mice lacking c-Jun in the liver (c-jun (Deltali*)) display impaired liver regeneration after partial hepatectomy (PH). This phenotype correlates with increased protein levels of the cdk-inhibitor p21 in the liver. We performed PH experiments in several double-knockout mouse models to genetically identify the signaling events regulated by c-Jun. Inactivation of p53 in c-jun (Deltali*) mice abrogated both hepatocyte cell cycle block and increased p21 protein expression. Consistently, liver regeneration was rescued in c-jun (Deltali*) p21 (-/-) double-mutant mice. This indicated that c-Jun controls hepatocyte proliferation by a p53/p21-dependent mechanism. Analyses of p21 mRNA and protein expression in livers of c-jun (Deltali*) mice after PH revealed that the accumulation of p21 protein is due to a post-transcriptional/post-translational mechanism. We have investigated several candidate pathways implicated in the regulation of p21 expression, and observed increased activity of the stress kinase p38 in regenerating livers of c-jun (Deltali*) mice. Importantly, conditional deletion of p38alpha in livers of c-jun (Deltali*) mice fully restored hepatocyte proliferation and attenuated increased p21 protein levels after PH. These data demonstrate that c-Jun/AP-1 regulates liver regeneration through a novel molecular pathway that involves p53, p21, and the stress kinase p38alpha.
 ...
PMID:c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. 1691 79

The immediate early gene pip92 is rapidly and transiently induced by serum, basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and phobol ester, as well as various toxic stimuli. Rho GTPases, such as RhoA, Rac1 and Cdc42, have been implicated in both cytoskeletal rearrangement and cell cycle control. Rac1 and Cdc42 induce neurite outgrowth in many types of neuronal cells. A downstream effector of both Rac1 and Cdc42, p21-activated kinase (Pak1), is highly enriched in neurons. In the present study, we examined the signal transduction pathways involved in pip92 induction, focusing on the involvement of Rho family guanosine 5'-triphosphate (GTP)ases. We also examined the functional role of pip92 expression during FGF-induced neuronal differentiation in embryonic hippocampal cells. Significant and robust activation of c-Jun N-terminal Kinase (JNK), Rac1 and extracellular signal-regulated kinase (ERK) appeared to be important for pip92 induction in response to bFGF. Transient transfection of kinase-inactive MEKK7 or chemical inhibitors of JNK significantly decreased the activation of Rac1 by FGF. However, blockade of Rac1 did not affect JNK activity. Moreover, a MEK-ERK blockade did not affect Rac1 activity. Activation of JNK and Rac1 induced Pak1 activity, which could then phosphorylate and activate transcription factor Elk1. Stimulation of Pak1-dependent Elk1 was required for the bFGF-induced activation of pip92. Suppression of endogenous pip92 expression by siRNA significantly enhanced bFGF-induced neurite outgrowth, while the ectopic expression of pip92 suppressed the neurite extension. Taken together, these data suggest that neurogenic growth factor-induced expression of pip92 is critical for the regulation of neuronal differentiation, occurring through the subsequent activation of Rac1, JNK, Pak1 and Elk1.
 ...
PMID:JNK- and Rac1-dependent induction of immediate early gene pip92 suppresses neuronal differentiation. 1715 31

c-Jun NH(2)-terminal kinase (JNK), a member of the MAPK family of protein kinases, is a stress-response kinase that is activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through nonreceptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We recently demonstrated that the activation of JNK by this condition is initiated by ROI generated by mitochondrial electron transport and involves sequential activation of the proline-rich kinase 2 and the small GTP-binding factors Rac-1 and Cdc42. Here we present evidence that protein kinase C (PKC) and transforming growth factor-beta-activated kinase-1 (TAK-1) are also components of this pathway. Inhibition of PKC with the broad-range inhibitor calphostin C, the PKC-alpha/beta-selective inhibitor Go9367, or adenovirus-expressing dominant-negative PKC-alpha blocked the phosphorylation of proline-rich kinase 2 and JNK. Reoxygenation activated the mitogen-activated protein kinase kinase kinase, TAK-1, and promoted the formation of a complex containing Rac-1, TAK-1, and JNK but not apoptosis-stimulating kinase-1 or p21-activated kinase-1, which was detected within the first 10 min of reoxygenation. These results identify two new components, PKC and TAK-1, that have not been previously described in this signaling pathway.
 ...
PMID:PKC-alpha and TAK-1 are intermediates in the activation of c-Jun NH2-terminal kinase by hypoxia-reoxygenation. 1720 6

The c-Jun/Sp1 interaction is essential for growth factor- and phorbol 12-myristate 13-acetate (PMA)-induced genes expression, including human 12(S)-lipoxygenase, keratin 16, cytosolic phospholipase A2, p21(WAF1/CIP1), and neuronal nicotinic acetylcholine receptor beta4. Here, we examined the mechanism underlying the PMA-induced regulation on the interaction between c-Jun and Sp1. We found that treatment of cells with PMA induced a dephosphorylation at the C terminus of c-Jun at Ser-243 and a concomitant inhibition of PP2B by using PP2B small interfering RNA, resulting in reduction of PMA-induced gene expression as well as the c-Jun/Sp1 interaction. The c-Jun mutant TAM-67-3A, which contains three substitute alanines at Thr-231, Ser-243, and Ser-249 compared with TAM-67, binds more efficaciously with Sp1 and is about twice as efficacious as TAM-67 in inhibiting the PMA-induced activation of the 12(S)-lipoxygenase promoter. Importantly, PP2B not only dephosphorylates the c-Jun at Ser-243 but also interacts with c-Jun in PMA-treated cells. PMA stimulates the association of the PP2B/c-Jun/Sp1 complex with the promoter. These findings indicate the dephosphorylation of c-Jun C terminus is required for the c-Jun/Sp1 interaction and reveal that PP2B plays an important role in regulating c-Jun/Sp1 interaction in PMA-induced gene expression.
 ...
PMID:PP2B-mediated dephosphorylation of c-Jun C terminus regulates phorbol ester-induced c-Jun/Sp1 interaction in A431 cells. 1721 18

Our previous studies demonstrated that sulindac, a non-steroidal anti-inflammatory drug, suppressed intestinal tumor formation in mouse, which is linked to the induction of wild-type p53-activated fragment 1 (p21WAF1, or p21). Here we showed that sulindac also required c-Jun N-terminal Kinase 1 (JNK1) to inhibit cell proliferation and induce apoptosis in vitro and in vivo. First, sulindac inhibited cell proliferation and induced apoptosis in colon cancer cell lines HCT116 with wild-type p21 or null p21, which were p21-dependent and were also associated with the induction of p21 and phosphorylation of JNK1. Second, sulindac increased apoptosis in JNK1(+/+) and JNK1(-/-) mouse embryonic fibroblast (MEF) cells, but, the increase of apoptosis in JNK1(+/+) cells was more than that in JNK1(-/-) cells. More interestingly, sulindac significantly inhibited cell proliferation in JNK1(+/+) cells, but the inhibition in JNK1(-/-) cells markedly decreased. Further studies indicated that JNK1 was dramatically induced by sulindac in the JNK1(+/+) cells which correlated with the induction of p21. However, the induction of p21 in JNK1(-/-) cells was less than that in JNK1(+/+) cells. Finally, we determined the expression of JNK1 in the intestinal mucosa of Apc(+/-), p21(+/+) mice, and found that sulindac significantly induced JNK1 phosphorylation, corresponding to the induction of p21, both in mRNA and protein levels. Our data indicates that sulindac-mediated proliferation inhibition and apoptosis induction were not only p21-dependent, but also required JNK1.
 ...
PMID:JNK1 is required for sulindac-mediated inhibition of cell proliferation and induction of apoptosis in vitro and in vivo. 1729 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>