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)

RRR-alpha-tocopherol succinate (vitamin E succinate, VES) is a potent, selective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell culture and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK), but not p38, are critical mediators in VES-induced apoptosis of human breast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ERK1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of the substrate glutathione S-transferase-c-Jun and inhibited VES-induced apoptosis. Increased phosphorylation and transactivation activity of nuclear transcription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatments; however, only c-Jun and ATF-2 appear to be involved in VES-induced apoptosis based on antisense blockage experiments. Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. 1152 56

Keratins 8 (K8) and 18 are the primary intermediate filaments of simple epithelia. Phosphorylation of keratins at specific sites affects their organization, assembly dynamics, and their interaction with signaling molecules. A number of keratin in vitro and in vivo phosphorylation sites have been identified. One example is K8 Ser-73, which has been implicated as an important phosphorylation site during mitosis, cell stress, and apoptosis. We show that K8 is strongly phosphorylated on Ser-73 upon stimulation of the pro-apoptotic cytokine receptor Fas/CD95/Apo-1 in HT-29 cells. Kinase assays showed that c-Jun N-terminal kinase (JNK) was also activated with activation kinetics corresponding to that of K8 phosphorylation. Furthermore, K8 was also phosphorylated on Ser-73 by JNK in vitro, yielding similar phosphopeptide maps as the in vivo phosphorylated material. In addition, co-immunoprecipitation studies revealed that part of JNK is associated with K8 in vivo, correlating with decreased ability of JNK to phosphorylate the endogenous c-Jun. Taken together, K8 is a new cytoplasmic target for JNK in Fas receptor-mediated signaling. The functional significance of this phosphorylation could relate to regulation of JNK signaling and/or regulation of keratin dynamics.
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PMID:The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. 1178 24

We have found that ecteinascidin-743 (ET-743) inhibited cell proliferation at 1-10 ng/ml, leading to S and G(2)/M arrest and subsequent apoptosis, and induced early apoptosis without previous cell cycle arrest at 10-100 ng/ml in cancer cells. ET-743-mediated apoptosis, did not involve Fas/CD95. ET-743 induced c-Jun NH(2)-terminal kinase (JNK) and caspase-3 activation, and JNK and caspase inhibition prevented ET-743-induced apoptosis. ET-743 failed to promote apoptosis in caspase-3-deficient MCF-7 cells, further implicating caspase-3 in its proapoptotic action. Overexpression of bcl-2 by gene transfer abrogated ET-743-induced apoptosis, but cells underwent cell cycle arrest. ET-743 triggered cytochrome c release from mitochondria that was inhibited by Bcl-2 overexpression. Inhibition of transcription or protein synthesis did not prevent ET-743-induced apoptosis, but abrogated ET-743-induced cell cycle arrest. Microarray analyses revealed changes in the expression of a small number of cell cycle-related genes (p21, GADD45A, cyclin G2, MCM5, and histones) that suggested their putative involvement in ET-743-induced cell cycle arrest. These data indicate that ET-743 is a very potent anticancer drug showing dose-dependent cytostatic and proapoptotic effects through activation of two different signaling pathways, namely a transcription-dependent pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis that involves mitochondria, JNK, and caspase-3.
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PMID:Differential cytostatic and apoptotic effects of ecteinascidin-743 in cancer cells. Transcription-dependent cell cycle arrest and transcription-independent JNK and mitochondrial mediated apoptosis. 1219 19

The effect of hyperosmolarity on CD95 membrane targeting and CD95 ligand (CD95L)-induced apoptosis was studied in rat hepatocytes. CD95 showed a predominant intracellular localization in normoosmotically exposed rat hepatocytes, whereas hyperosmotic exposure induced, within 1 hour, CD95 trafficking to the plasma membrane followed by activation of caspase-3 and -8. Hyperosmotic CD95 membrane targeting was sensitive to inhibition of c-Jun-N-terminal kinase (JNK), protein kinase C (PKC), and cyclic adenosine monophosphate, but not to inhibition of extracellular regulated kinases (Erks) or p38 mitogen activated protein kinase (p38(MAPK)). Hyperosmotic CD95 targeting to the plasma membrane was dose-dependently diminished by glutamine or taurine, probably caused by an augmentation of volume regulatory increase. Despite CD95 trafficking to the plasma membrane and caspase activation, hyperosmolarity per se did not induce apoptosis. Hyperosmolarity, however, sensitized hepatocytes toward CD95L-induced apoptosis, as assessed by annexin V staining and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling (TUNEL) assay. This sensitization was abolished when hyperosmotic CD95 membrane trafficking was prevented by cyclic adenosine monophosphate, PKC, or JNK inhibition, whereas these effectors had no effect on CD95L-induced apoptosis in normoosmotically exposed hepatocytes. CD95L addition under normoosmotic conditions caused CD95 membrane trafficking, which was sensitive to JNK inhibition, but not to cyclic adenosine monophosphate or inhibition of PKC, Erks, and p38(MAPK). In conclusion, multiple signaling pathways are involved in CD95 membrane trafficking. Hyperosmotic hepatocyte shrinkage induces CD95 trafficking to the plasma membrane, which involves JNK-, PKA-, and PKC-dependent mechanisms and sensitizes hepatocytes toward CD95L-mediated apoptosis.
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PMID:Hyperosmolarity triggers CD95 membrane trafficking and sensitizes rat hepatocytes toward CD95L-induced apoptosis. 1219 52

Fas-associated death domain (FADD) plays an important role as an adapter molecule in Fas (CD95/APO-1)-mediated apoptosis and contributes to anticancer drug-induced cytotoxicity. We treated three human prostate cancer cell lines with etoposide, a toposiomerase II inhibitor with activity against various tumors including prostate cancer. We found that the overexpression of FADD sensitizes etoposide-induced apoptosis through a rapid activation of c-Jun NH(2)-terminal kinase (JNK) and, subsequently, of caspase 3. In addition, phosphorylation of FADD at serine 194 coincided with this sensitization. Treatment with the caspase 3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), or overexpression of either mitogen-activated protein kinase kinase (MKK) 7 or Bcl-xL canceled FADD-mediated sensitization to etoposide-induced apoptosis. Moreover, treatment with the caspase 8 inhibitor, benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone (z-IETD-fmk), or overexpression of viral FLICE/caspase-8-inhibitory protein (FLIP) from equine herpesvirus type 2 E8 also had an inhibitory effect, supporting a major involvement of a caspase 8-dependent mitochondrial pathway. Interestingly, FADD was phosphorylated, and etoposide-induced JNK/caspase activation and apoptosis were enhanced in the cells arrested at G2/M transition, but not in those overexpressing mutant FADD, in which 194 serine was replaced by alanine. Our results demonstrate that phosphorylated FADD-dependent activation of the JNK/caspase pathway plays a pivotal role in sensitization to etoposide-induced apoptosis in prostate cancer cells.
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PMID:Phosphorylation of Fas-associated death domain contributes to enhancement of etoposide-induced apoptosis in prostate cancer cells. 1241 47

Apoptosis is a highly regulated process that plays a critical role in neuronal development as well as the homeostasis of the adult nervous system. Vanadate, an environmental toxicant, causes developmental defects in the central nervous system. Here, we demonstrated that vanadate induced apoptosis in cultured cerebellar granule progenitors (CGPs). Treatment of cultured CGPs with vanadate activated ERKs and JNKs but not p38 MAPK and also induced c-Jun phosphorylation. In addition, vanadate induced FasL production, Fas (CD95) aggregation, and its association with the Fas-associated death domain (FADD), as well as the activation of caspase-8. Furthermore, vanadate generated reactive oxygen species (ROS) in CGPs; however, ROS was not involved in vanadate-mediated MAPK activation. Vanadate-induced FasL expression was ROS-dependent but JNK-independent. In contrast, vanadate-elicited Fas aggregation and Fas-FADD association, as well as caspase-8 activation, were dependent on JNK activation but were minimally regulated by ROS generation. The hydrogen peroxide scavenger, catalase, blocked vanadate-induced FasL expression and partially mitigated vanadate-induced cell death. On the other hand, dominant negative FADD and caspase-8 inhibitor completely eliminated vanadate-induced apoptosis. Thus, JNK signaling plays a major role in vanadate-mediated activation of the Fas-FADD-caspase-8 pathway that accounts for vanadate-induced apoptosis of CGPs.
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PMID:Activation of JNK by vanadate induces a Fas-associated death domain (FADD)-dependent death of cerebellar granule progenitors in vitro. 1245 17

The mechanisms underlying CD95 ligand (CD95L)- and hyperosmolarity-induced activation of the CD95 system [Reinehr, R., Graf, D., Fischer, R., Schliess, F., and Haussinger, D. (2002) Hepatology 36, 602-614] as initial steps of apoptosis were studied. Hyperosmotic exposure (405 mosmol/l) of rat hepatocytes induced within 1 min oxidative stress and antioxidant-sensitive activation of the epidermal growth factor receptor (EGFR) and c-Jun-N-terminal-kinase (JNK). After 30 min of hyperosmotic exposure EGFR associated with CD95 and CD95 became tyrosine phosphorylated. Inhibition of JNK or protein kinase C (PKC) had no effect on EGFR phosphorylation but abolished CD95/EGFR association, CD95-tyrosine phosphorylation, membrane targeting, and Fas-associated death domain/caspase 8 recruitment to CD95 [death-inducing signaling complex (DISC) formation]. Inhibition of EGFR tyrosine kinase activity prevented CD95 tyrosine phosphorylation and DISC formation but not hyperosmolarity-induced EGFR phosphorylation and EGFR association with CD95. Tyrosine-phosphorylated CD95 was enriched in the plasma membrane. All maneuvers preventing CD95 tyrosine phosphorylation inhibited CD95 membrane trafficking and DISC formation. Stimulation of EGFR by EGF induced EGFR phosphorylation but no association with CD95 or CD95 phosphorylation. Addition of CD95L also induced EGFR and JNK activation, EGFR/CD95 association, CD95 tyrosine phosphorylation, DISC formation, and CD95 membrane targeting with an inhibitor sensitivity profile similar to that of hyperosmotic CD95 activation, except that inhibition of PKC was ineffective. The data suggest that moderate hyperosmolarity or CD95L trigger oxidative stress and EGFR activation followed by a JNK-dependent EGFR/CD95association and CD95 tyrosine phosphorylation, probably through EGFR tyrosine kinase activity. This provides a signal for CD95 membrane trafficking and DISC formation.
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PMID:Hyperosmolarity and CD95L trigger CD95/EGF receptor association and tyrosine phosphorylation of CD95 as prerequisites for CD95 membrane trafficking and DISC formation. 1258 32

The CD95 (APO-1/Fas) system plays a major role in induction of apoptosis in lymphoid and nonlymphoid tissues. The CD95 (APO-1/Fas) ligand (CD95L) is induced in response to a variety of signals including TCR/CD3 stimulation or application of chemotherapeutic drugs. Here we report that an AP-1 site located in the 5' untranslated region of the CD95L gene is required for TCR/CD3-mediated induction of the human CD95L promoter. Electrophoretic mobility shift assays using nuclear extracts of Jurkat T cells as well as TCR/CD3-restimulated primary human T cells demonstrated specific binding of AP-1, predominantly composed of c-Jun and FosB, to this sequence. Ectopic expression of transdominant negative Jun mutants strongly reduced CD95L promoter activity and activation-induced cell death (AICD), confirming the functional significance of FosB/c-Jun binding. Thus, our results demonstrate an important novel function for FosB dimerized with c-Jun in TCR/CD3-mediated AICD in human T cells.
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PMID:An unexpected role for FosB in activation-induced cell death of T cells. 1261 58

Aplidine is a promising antitumor agent derived from the Mediterranean tunicate Aplidium albicans. We have found that Aplidine at nM concentrations (10-100 nM) induced apoptosis in human leukemic cell lines and primary leukemic cell cultures from leukemic patients. Inhibition of the Fas (CD95)/Fas ligand (CD95L) signaling pathway with an antagonistic anti-Fas antibody partially inhibited Aplidine-induced apoptosis. L929 cells were resistant to Aplidine action but underwent apoptosis after transfection with human Fas cDNA. Aplidine induced a rapid and sustained c-Jun NH(2)-terminal kinase activation, and pretreatment with curcumin or SP600125 inhibited Aplidine-induced c-Jun NH(2)-terminal kinase activation and apoptosis. However, inhibition of extracellular signal-regulated kinase and p38 kinase signaling pathways did not affect Aplidine-induced apoptosis. Aplidine induced caspase-3 activation, and caspase inhibition prevented Aplidine-induced apoptosis. Aplidine failed to induce apoptosis in MCF-7 breast cancer cells, defective in caspase-3, additionally implicating caspase-3 in its proapoptotic action. Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis. Aplidine rapidly induced cleavage of Bid, a mediator that connects the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. Primary cultures of normal human cells, including hepatocytes and resting peripheral blood lymphocytes, were spared or weakly affected after Aplidine treatment. Nevertheless, mitogen (phytohemagglutinin/interleukin-2)-activated T lymphocytes resulted sensitively to the apoptotic action of Aplidine. Thus, Aplidine is an extremely potent and rapid apoptotic inducer on leukemic cells that triggers Fas/CD95- and mitochondrial-mediated apoptotic signaling routes, and shows a rather selective apoptotic action on cancer cells and activated T cells.
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PMID:Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. 1268 30

Previous studies have identified RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) as a potential chemotherapeutic agent. VES induces human breast cancer cells to undergo apoptosis in a concentration- and time-dependent manner by restoring transforming growth factor beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways, that contribute to the activation of c-Jun NH(2)-terminal kinase (JNK)-mediated apoptosis. The objective of these studies was to clarify biochemical events involved in VES-induced apoptosis. Data show that VES-induced apoptosis involves: (a) translocation of Bax from the cytosol to the mitochondria and cytochrome c release from the mitochondria to the cytosol as determined by Western immunoblot analyses of mitochondrial- and cytosolic-enriched cellular fractions; (b) increased permeabilization of mitochondrial membranes as determined by confocal and fluorescence-activated cell sorting analyses of loss of a mitochondrial selective fluorescent dye; (c) processing of caspase-9 and -3 but not caspase-8 to active forms and cleavage of poly(ADP-ribose) polymerase (PARP) as determined by Western immunoblot analyses using antibodies capable of detecting both proenzyme and processed enzyme forms or the intact or cleaved forms of PARP. Transient transfection of cells with antisense oligonucleotides to Bax or transient overexpression of Bcl-2 prevented VES-induced mitochondrial permeability transition and apoptosis. The use of cell-permeable caspase inhibitors indicated that caspase-9 and -3 but not caspase-8 are involved in VES-induced apoptosis. JNK inhibitor II blocked VES-induced Bax conformational change, indicating a role for JNK in Bax translocation to the mitochondria. Taken together, these data suggest that the activation of JNK, translocation of Bax to the mitochondria, increased mitochondrial membrane permeability with release of cytochrome c, and activation of caspase-9 and -3 are critical events in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. 1275 Feb 70


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