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)

Ansamycin antibiotics that target heat shock protein 90 function are being developed as anticancer agents but are also known to be dose limiting in patients due to hepatotoxicity. Herein, to better understand how the normal tissue toxicity of geldanamycins could be ameliorated to improve the therapeutic index of these agents, we examined the interactions of 17-allylamino-17-demethoxygeldanamycin (17AAG) and the secondary bile acid deoxycholic acid (DCA) in hepatocytes and fibroblasts. DCA and 17AAG interacted in a greater than additive fashion to cause hepatocyte cell death within 2 to 6 h of coadministration. As single agents DCA, but not 17AAG, enhanced the activity of extracellular signal-regulated kinase 1/2, AKT, c-Jun NH(2)-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (MAPK). Combined exposure of cells to DCA and 17AAG further enhanced JNK1/2 and p38 MAPK activity. Inhibition of JNK1/2 or p38 MAPK, but not activator protein-1, suppressed the lethality of 17AAG and of 17AAG and DCA. Constitutive activation of AKT, but not MAPK/extracellular signal-regulated kinase kinase 1/2, suppressed 17AAG- and DCA-induced cell killing and reduced activation of JNK1/2. DCA and 17AAG exposure promoted association of BAX with mitochondria, and functional inhibition of BAX or caspase-9, but not of BID and caspase-8, suppressed 17AAG and DCA lethality. DCA and 17AAG interacted in a greater than additive fashion to promote and prolong the generation of reactive oxygen species (ROS). ROS-quenching agents, inhibition of mitochondrial function, expression of dominant-negative thioredoxin reductase, or expression of dominant-negative apoptosis signaling kinase 1 suppressed JNK1/2 and p38 MAPK activation and reduced cell killing after 17AAG and DCA exposure. The potentiation of DCA-induced ROS production by 17AAG was abolished by Ca(2+) chelation and ROS generation, and cell killing following 17AAG and DCA treatment was abolished in cells lacking expression of PKR-like endoplasmic reticulum kinase. Thus, DCA and 17AAG interact to stimulate Ca(2+)-dependent and PKR-like endoplasmic reticulum kinase-dependent ROS production; high levels of ROS promote intense activation of the p38 MAPK and JNK1/2 pathways that signal to activate the intrinsic apoptosis pathway.
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PMID:17-Allylamino-17-demethoxygeldanamycin enhances the lethality of deoxycholic acid in primary rodent hepatocytes and established cell lines. 1730 59

Exposure of tumor cells to clinically relevant doses of ionizing radiation causes DNA damage as well as mitochondria-dependent generation of reactive oxygen species. DNA damage causes activation of ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3-related protein, which induce cell cycle checkpoints and also modulate the activation of prosurvival and proapoptotic signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH(2)-terminal kinase 1/2, respectively. Radiation causes a rapid reactive oxygen species-dependent activation of ERBB family and other tyrosine kinases, leading to activation of RAS proteins and multiple protective downstream signaling pathways (e.g., AKT and ERK1/2), which alter transcription factor function and the apoptotic threshold of cells. The initial radiation-induced activation of ERK1/2 can promote the cleavage and release of paracrine ligands, which cause a temporally delayed reactivation of receptors and intracellular signaling pathways in irradiated and unirradiated bystander cells. Hence, signals from within the cell can promote activation of membrane-associated receptors, which signal back into the cytosol: signaling from inside the cell outward to receptors and then inward again via kinase pathways. However, cytosolic signaling can also cause release of membrane-associated paracrine factors, and thus, paracrine signals from outside of the cell can promote activation of growth factor receptors: signaling from the outside inward. The ultimate consequence of these signaling events after multiple exposures may be to reprogram the irradiated and affected bystander cells in terms of their expression levels of growth-regulatory and cell survival proteins, resulting in altered mitogenic rates and thresholds at which genotoxic stresses cause cell death. Inhibition of signaling in one and/or multiple survival pathways enhances radiosensitivity. Prolonged inhibition of any one of these pathways, however, gives rise to lineages of cells, which have become resistant to the inhibitor drug, by evolutionary selection for the clonal outgrowth of cells with point mutations in the specific targeted protein that make the target protein drug resistant or by the reprogramming of multiple signaling processes within all cells, to maintain viability. Thus, tumor cells are dynamic with respect to their reliance on specific cell signaling pathways to exist and rapidly adapt to repeated toxic challenges in an attempt to maintain tumor cell survival.
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PMID:Radiation-induced cell signaling: inside-out and outside-in. 1736 76

We and other investigators have previously shown that membrane-type 1 matrix metalloproteinase (MT1-MMP) is overexpressed in invasive prostate cancer cells. However, the mechanism for this expression is not known. Here, we show that MT1-MMP is minimally expressed in nonmalignant primary prostate cells, moderately expressed in DU-145 cells, and highly expressed in invasive PC-3 and PC-3N cells. Using human MT1-MMP promoter reporter plasmids and mobility shift assays, we show that Sp1 regulates MT1-MMP expression in DU-145, PC-3, and PC-3N cells and in PC3-N cells using chromatin immunoprecipitation analysis and silencing RNA. Investigation of signaling pathway showed that DU-145 cells express constitutively phosphorylated extracellular stress-regulated kinase (ERK), whereas PC-3 and PC-3N cells express constitutively phosphorylated AKT/PKB and c-Jun NH2 terminal kinase (JNK). We show that MT1-MMP and Sp1 levels are decreased in PC-3 and PC-3N cells when phosphatidylinositol-3 kinase and JNK are inhibited, and that MT1-MMP levels are decreased in DU-145 cells when MEK is inhibited. Transient transfection of PC-3 and PC-3N cells with a dominant-negative JNK or p85, and of DU-145 cells with a dominant negative ERK, reduces MT1-MMP promoter activity. These results indicate differential signaling control of Sp1-mediated transcriptional regulation of MT1-MMP in prostate cancer cell lines.
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PMID:Membrane-type 1 matrix metalloproteinase is regulated by sp1 through the differential activation of AKT, JNK, and ERK pathways in human prostate tumor cells. 1753 46

Protein kinase Cdelta (PKCdelta) regulates cell apoptosis and survival in diverse cellular systems. PKCdelta translocates to different subcellular sites in response to apoptotic stimuli; however, the role of its subcellular localization in its proapoptotic and antiapoptotic functions is just beginning to be understood. Here, we used a PKCdelta constitutively active mutant targeted to the cytosol, nucleus, mitochondria, and endoplasmic reticulum (ER) and examined whether the subcellular localization of PKCdelta affects its apoptotic and survival functions. PKCdelta-Cyto, PKCdelta-Mito, and PKCdelta-Nuc induced cell apoptosis, whereas no apoptosis was observed with the PKCdelta-ER. PKCdelta-Cyto and PKCdelta-Mito underwent cleavage, whereas no cleavage was observed in the PKCdelta-Nuc and PKCdelta-ER. Similarly, caspase-3 activity was increased in cells overexpressing PKCdelta-Cyto and PKCdelta-Mito. In contrast to the apoptotic effects of the PKCdelta-Cyto, PKCdelta-Mito, and PKCdelta-Nuc, the PKCdelta-ER protected the cells from tumor necrosis factor-related apoptosis-inducing ligand-induced and etoposide-induced apoptosis. Moreover, overexpression of a PKCdelta kinase-dead mutant targeted to the ER abrogated the protective effect of the endogenous PKCdelta and increased tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. The localization of PKCdelta differentially affected the activation of downstream signaling pathways. PKCdelta-Cyto increased the phosphorylation of p38 and decreased the phosphorylation of AKT and the expression of X-linked inhibitor of apoptosis protein, whereas PKCdelta-Nuc increased c-Jun NH(2)-terminal kinase phosphorylation. Moreover, p38 phosphorylation and the decrease in X-linked inhibitor of apoptosis protein expression played a role in the apoptotic effect of PKCdelta-Cyto, whereas c-Jun NH(2)-terminal kinase activation mediated the apoptotic effect of PKCdelta-Nuc. Our results indicate that the subcellular localization of PKCdelta plays important roles in its proapoptotic and antiapoptotic functions and in the activation of downstream signaling pathways.
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PMID:The localization of protein kinase Cdelta in different subcellular sites affects its proapoptotic and antiapoptotic functions and the activation of distinct downstream signaling pathways. 1757 21

The steroid receptor coactivator amplified in breast cancer 1 (AIB1) as well as epidermal growth factor receptor (EGFR) family members are frequently overexpressed in epithelial tumors, and their expression is associated with poor prognosis. However, a direct role of AIB1 in EGF signaling has not been determined. To address this, we reduced endogenous AIB1 levels using RNA interference in lung, breast, and pancreatic cancer cell lines. We found that a knockdown of AIB1 levels resulted in a loss of the growth response of these cell lines to EGF. Further analysis revealed that the depletion of AIB1 reduced tyrosine phosphorylation of EGFR at multiple residues both at autophosphorylation and Src kinase phosphorylation sites. AIB1 knockdown did not affect tyrosine phosphorylation of the receptor tyrosine kinases, platelet-derived growth factor receptor and HER3, or overall tyrosine phosphorylation of cellular proteins. However, EGF-dependent phosphorylation of HER2 was decreased. EGFR levels and membrane trafficking were not changed by AIB1 depletion, but there was less recruitment of Src homology 2 domain-containing proteins to the EGFR. This led to a substantial reduction in EGF-induced phosphorylation of signal transducers and activators of transcription 5 and c-Jun NH(2)-terminal kinase but no significant change in the activation of AKT. Vanadate treatment of cells revealed that the reduction in EGFR tyrosine phosphorylation is dependent in part on changes in cellular phosphatase activity. We propose that a portion of the oncogenic effect of AIB1 could be through control of EGFR and HER2 activity and subsequent modulation of cellular signaling pathways.
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PMID:Epidermal growth factor receptor tyrosine phosphorylation and signaling controlled by a nuclear receptor coactivator, amplified in breast cancer 1. 1767 Nov 94

Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAi) and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf(V600E) expression strongly suppressed the anchorage-dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B-RAF mutation-positive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH(2)-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas.
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PMID:Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth. 1769 19

Melanoma is the most aggressive skin cancer and a serious health problem worldwide because of its increasing incidence and the lack of satisfactory chemotherapy for late stages of the disease. The marine depsipeptide Aplidin (plitidepsin) is an antitumoral agent under phase II clinical development against several neoplasias, including melanoma. We report that plitidepsin has a dual effect on the human SK-MEL-28 and UACC-257 melanoma cell lines; at low concentrations (</=45 nM), it inhibits the cell cycle by inducing G(1) and G(2)/M arrest, whereas at higher concentrations it induces apoptosis as assessed by poly-(ADP-ribose) polymerase cleavage and the appearance of a hypodiploid peak in flow cytometry analyses. Plitidepsin activates Rac1 GTPase and c-Jun NH(2)-terminal kinase (JNK). In addition, it induces AKT and p38 mitogen-activated protein kinase (MAPK) phosphorylation. By using inhibitors, we found that JNK and p38 MAPK activation depends on Rac1 but not on phosphatidylinositol 3-kinase (PI3K), whereas AKT activation is independent of Rac1 but requires PI3K activity. Plitidepsin cytotoxicity diminishes by Rac1 inhibition or by the blockage of JNK and p38 MAPK using 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), but not by PI3K inhibition using wortmannin or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). It is remarkable that plitidepsin and dacarbazine, the alkylating agent most active for treating metastatic melanoma, show a synergistic antiproliferative effect that was paralleled at the level of JNK activation. These results indicate that Rac1/JNK activation is critical for cell cycle arrest and apoptosis induction by plitidepsin in melanoma cells. They also support the combined use of plitidepsin and dacarbazine in in vivo studies.
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PMID:Plitidepsin has a dual effect inhibiting cell cycle and inducing apoptosis via Rac1/c-Jun NH2-terminal kinase activation in human melanoma cells. 1808 42

The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH(2)-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function.
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PMID:Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. 1828 16

NOV-002 is a novel glutathione disulfide mimetic that when administered in combination with standard chemotherapeutic regimens has resulted in increased efficacy (survival, tumor response) and improved tolerance to chemotherapy (e.g., hematologic recovery) in advanced non-small cell lung cancer patients. We show that NOV-002, which is not cytotoxic as a single agent, generated time- and concentration-dependent oxidative signals at the cell surface (reduction in protein thiols) and intracellularly [altered oxidized glutathione (GSSG) and reduced glutathione levels and ratio; increased reactive oxygen species] in the premyeloid HL-60 cell line and that this was associated with an increase in S-glutathionylation of cell proteins, particularly actin. Commensurate with these effects, NOV-002 activated p38, c-Jun-NH(2)-kinase, and extracellular signal-regulated kinase and caused a dose-dependent increase in phosphorylation of three proteins that have previously been linked with hematopoiesis, AKT, JAK2, and STAT5. The effect of NOV-002 on enzymes involved in glutathione metabolism was evaluated. Relative to oxidized glutathione, NOV-002 was an equivalent substrate for glutathione reductase and was an inhibitor of protein disulfide isomerase, one of the components of the redox-sensitive unfolded protein response pathway. These redox-stimulated cell signaling actions occurred in the context of increased HL-60 cell proliferation after treatment with NOV-002. Overall, the pleiotropic pharmacologic effects of NOV-002 can be attributed to the GSSG component of the drug, and modulation of cellular redox balance is a feature central to the mechanism of action of NOV-002. Such modulation may underlie its clinical actions, including hematologic recovery and immunostimulation in the face of chemosuppression.
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PMID:NOV-002, a glutathione disulfide mimetic, as a modulator of cellular redox balance. 1841 55

PEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKCdelta, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKCdelta was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKCalpha and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKCdelta and reduced expression of PKCalpha resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents.
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PMID:Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. 1841 5


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