Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heregulins are a group of growth factors that play diverse and critical roles in the signaling network of the human epidermal growth factor receptor (HER or EGFR) superfamily. Our earlier studies have shown that recombinant heregulinbeta1 (HRG) induces apoptosis in SKBr3 breast cancer cells that overexpress HER2. Here we report molecular mechanisms of HRG-induced apoptosis. HRG treatment of SKBr3 cells for 72 h decreased the level of Bcl-2 protein. HRG treatment led to degradation of poly (ADP-ribose) polymerase (PARP) and activated both caspase-9 and caspase-7. No significant activation of caspase-3, -6, or -8 was detected. Expression of exogenous caspase-7 by adenovirus-caspase-7 (Ad-casp-7) in SKBr3 cells resulted in apoptosis, which mimicked the effect of HRG treatment. Expression of exogenous caspase-7 had no impact on Bcl-2 expression, but promoted PARP degradation. Two highly selective inhibitors of protein kinase C (PKC), GF109203X (GF) and Ro318425 (Ro), significantly enhanced HRG-induced apoptosis as determined by flow cytometric analysis and DNA fragmentation assay. Accordingly, the PKC inhibitor GF further decreased the level of Bcl-2 protein and further degraded PARP in HRG-treated cells. Assay of PKC activity indicated that HRG activated PKC in SKBr3 cells, predominantly affecting the PKCalpha isoform. To confirm which PKC isoform(s) mediated potentiation of HRG-induced apoptosis, the profile of PKC isoforms was measured in SKBr3 cells. Five PKC isoforms, PKCalpha, PKCiota, PKCzeta, PKClambda, and PKCdelta as well as their receptors (RACK1) were expressed in this cell line. Treatment with PKC inhibitors GF and Ro decreased protein levels of both PKCalpha and PKCdelta at 24 h. PKCalpha levels were still depressed at 72 h. GF and Ro had little effect on the expression of other PKC isoforms. An inhibitor of classical PKC isoforms (Go6976) enhanced HRG-induced apoptosis, whereas the PKCdelta selective inhibitor rottlerin did not. As PKCalpha was the only classical isoform expressed in SKBr3 cells, the effect of Go6976 on HRG-induced apoptosis largely related to inhibition of PKCalpha. Constitutive expression of wild-type PKCalpha attenuated the apoptosis produced by HRG and GF. Consequently, HRG-induced apoptosis in SKBr3 cells appeared to involve down-regulation of Bcl-2 protein, activation of caspase-9 and caspase-7, and degradation of PARP. Inhibition of PKC function enhanced HRG-induced apoptosis, leading to synergistic down-regulation of Bcl-2 expression. Impairment of the PKCalpha isoform alone was sufficient to potentiate HRG-induced apoptosis.
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PMID:Heregulin-induced apoptosis is mediated by down-regulation of Bcl-2 and activation of caspase-7 and is potentiated by impairment of protein kinase C alpha activity. 1178 40

Herpes simplex virus type 1 (HSV-1) triggered apoptosis in hippocampal cultures, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry with antibody specific for the large fragment of activated caspase 3. The levels of phosphorylated (activated) c-Jun N-terminal kinase (JNK) were also increased in HSV-1-infected hippocampal cultures as were the levels of activated c-Jun, its target. JNK activation was involved in HSV-1-induced apoptosis as evidenced by apoptosis inhibition with the JNK inhibitor SP600125. HSV-2 activated the mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) survival pathway and did not trigger apoptosis in hippocampal cultures. The MEK specific inhibitor U0126 inhibited ERK activation and caused a significant increase in the percent TUNEL(+) cells in HSV-2-infected cultures, indicating that the failure of HSV-2 to trigger apoptosis is due to its ability to activate the MEK/ERK survival pathway. JNK was also activated in brain tissues from patients with HSV-associated acute focal encephalitis (HSE) that were positive for HSV-1 antigen. JNK activation correlated with apoptosis, as determined by immunohistochemistry with antibody to activated caspase 3 or cleaved poly (ADP-ribose) polymerase (PARP). The data suggest that HSE has an apoptotic component that may contribute to disease pathogenesis.
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PMID:Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase. 1258 73

Ginseng (the root of Panax ginseng C.A. Meyer, Araliaceae) has been used as a crude drug taken orally for preventive and therapeutic purposes in Asian countries as a traditional medicine. In the current study, we have investigated the antitumor effect of a novel ginseng protopanaxadiol saponin bacterial metabolic derivative, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (IH-901), in eight human myeloma cell lines. IH-901 inhibited the proliferation of all myeloma cell lines examined. Despite the fibroblast growth factor receptor 3 (FGFR3) overexpression due to a chromosomal translocation t(4;14)(q16.3;q32.3) in KMS-11 myeloma cells, IH-901 induced apoptosis in a dose- and time-dependent way in this cell line. Treatment of KMS-11 with IH-901 resulted in the formation of internucleosomal DNA fragments, poly (ADP-ribose) polymerase cleavage, and the activation of caspase-3. IH-901 also caused the down-regulation of FGFR3 mRNA and protein expression and inhibited ERK activity in KMS-11 cells. Our results demonstrate that IH-901 induces apoptosis and inhibits FGFR3 expression and signaling in KMS-11 cells, suggesting candidacy for the chemoprevention and the treatment of myeloma.
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PMID:A novel ginseng saponin metabolite induces apoptosis and down-regulates fibroblast growth factor receptor 3 in myeloma cells. 1296 89

Although tamoxifen (TAM), which is widely used in the treatment of breast cancer, also has a beneficial effect on cisplatin-refractory ovarian cancer, the biological mechanism of this effect has remained obscure. TAM, besides its action as an antiestrogen, also inhibits cell proliferation of estrogen receptor (ER)-negative cells by an unknown mechanism. Therefore, we examined the roles of the MAPK family in the antiproliferative effect of TAM on cisplatin-resistant Caov-3, which expresses ER and cisplatin-sensitive A2780, which does not express ER. The number of viable cells was reduced by TAM dose-dependently. TAM induced the activation of ERK, c-Jun N-terminal protein kinase (JNK), and p38 with different time courses. PD98059 canceled the reduction of the number of viable cells by 1 microM TAM and inhibited the TAM-induced cell-cycle arrest at the G(1) phase and dephosphorylation of the retinoblastoma protein. Either expression of dominant-negative JNK or pretreatment with SB203580 canceled the reduction of the number of viable cells by 5 microM TAM and inhibited the apoptotic nuclear changes and the cleavage of poly (ADP-ribose) polymerase induced by TAM. These results provide evidence that whereas the ERK cascade is involved in the induction of cell-cycle arrest at the G(1) phase by lower concentrations of TAM, the JNK or p38 cascade is involved in the induction of apoptosis by higher concentrations of TAM in both types of cells.
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PMID:Tamoxifen inhibits cell proliferation via mitogen-activated protein kinase cascades in human ovarian cancer cell lines in a manner not dependent on the expression of estrogen receptor or the sensitivity to cisplatin. 1464 10

Understanding the detailed mechanisms of a chemotherapeutic agent action on cancer cells is essential for planning the clinical applications because drug effects are often tissue and cell type specific. This study set out to elucidate the molecular pathways of Taxol effects in human anaplastic thyroid cancer cells using as an experimental model four cell lines, ARO, KTC-2, KTC-3 (anaplastic thyroid cancer), and FRO (undifferentiated follicular cancer), and primary thyrocytes. All cell lines were sensitive to Taxol, although to different extent. In primary thyrocytes the drug displayed substantially lower cytotoxicity. In thyroid cancer cells, Taxol-induced changes characteristic to apoptosis such as poly (ADP-ribose) polymerase and procaspase cleavage and alteration of membrane asymmetry only within a narrow concentration range, from 6 to 50 nm. At higher concentration, other form(s) of cell death perhaps associated with mitochondrial collapse was observed. Low doses of Taxol enhanced Bcl2 phosphorylation and led to its degradation observed on the background of a sustained or increasing Bax level and accumulation of survivin and X-chromosome-linked inhibitor of apoptosis. c-jun-NH(2) terminal kinase activation was essential for the apoptosis in anaplastic thyroid cancer cells, whereas Raf/MAPK kinase/ERK and phosphatidylinositol-3-OH kinase/Akt were likely to comprise main survival mechanisms. Our results suggest an importance of cautious interpreting of biological effects of Taxol in laboratory studies and for determining optimal doses of Taxol to achieve the desired therapeutic effect in anaplastic thyroid cancers.
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PMID:Molecular mechanisms of the effects of low concentrations of taxol in anaplastic thyroid cancer cells. 1504 68

The insulin-like growth factor-I receptor (IGF-IR) has an important role in colorectal cancer development and progression. IGF-IR displays a potent anti-apoptotic activity and is overexpressed in primary tumors and colon cancer-derived cell lines. Folic acid, a member of the vitamin B family, is a chemopreventive agent whose deficiency has been linked to an enhanced colon cancer risk. The present study was aimed at testing the hypothesis that part of the modulatory effect of folic acid on malignant transformation may be attributed to its ability to regulate IGF-IR gene expression. Regulation of IGF-IR gene expression by folic acid was assessed using western blots, RT-PCR, transient transfections and chromatin immunoprecipitation assays. Activation of the IGF-IR signaling pathway was evaluated by measuring phosphorylation of ERK, and apoptosis was assayed using poly (ADP-ribose) polymerase cleavage and annexin V-FITC staining. Results obtained showed that folic acid induced a dose-dependent decrease in IGF-IR protein and mRNA levels in the HCT116 +/+ colon cancer cell line. This effect was associated with a significant reduction in IGF-IR promoter activity. Similar effects were elicited by the folic acid metabolites dihydrofolic acid and tetrahydrofolic acid. In addition, folic acid abrogated the IGF-I-stimulated phosphorylation of the downstream signaling molecule ERK1/2 and exhibited a pro-apoptotic activity. Moreover, folic acid induced a significant decrease in Sp1 binding to the IGF-IR promoter region. Finally, folic acid had no effect in wild-type p53-depleted HCT116 -/- and Caco-2 cells. In conclusion, the mechanism of action of folic acid involves regulation of IGF-IR gene expression. The ability of folic acid to downregulate the IGF-I signal transduction pathway may allow the micronutrient to function as a chemopreventive agent. Folic acid deficiency, on the other hand, may lead to increased IGF-IR gene expression, with ensuing pathological activation by endocrine and/or autocrine/paracrine IGF-I.
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PMID:Folic acid and its metabolites modulate IGF-I receptor gene expression in colon cancer cells in a p53-dependent manner. 1672 83

SU11248 is an orally available type III and V receptor tyrosine kinase inhibitor. Clinical studies have shown the efficacy of SU11248 in individuals with gastrointestinal stromal tumors (GIST); however, the molecular mechanisms by which SU11248 inhibits the proliferation of these tumor cells remains to be fully elucidated. Taking advantage of GIST-T1 cells, which possess an activating mutation in exon 11 of the c-KIT gene, we examined the medicinal action of SU11248 in GIST cells. Clonogenic and MTT assays showed that SU11248 potently inhibited the proliferation of GIST-T1 cells with IC50 of approximately 1 nM and 40 nM, respectively. SU11248 (10 or 20 nM, 48 h) activated caspase-3 and induced apoptosis of GIST-T1 cells as measured by caspase assay, annexin V staining and cleavage of poly (ADP-ribose) polymerase. Western blot analyses found that SU11248 blocked autophosphorylation of c-KIT in association with inhibition of its downstream effectors, including Akt and extracellular signal-regulated kinase, but not signal transducers and activators of transcription. Interestingly, when phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling was blocked simultaneously by either LY294002 or rapamycin, growth inhibition mediated by SU11248 was potentiated. Taken together, this study supports clinical studies of SU11248 for individuals with GIST, and the combination of SU11248 and inhibitors of 3-kinase/Akt/mammalian target of rapamycin signaling represents a promising novel treatment strategy.
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PMID:Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling. 1691 20

We examined the impact of EGFR-ERK signaling on poly (ADP-ribose) polymerase (PARP) activation following ionizing irradiation of human prostate cancer (PCa) cell lines displaying marked differences in ERK dependence. PARP activation was indicated by the appearance of polyADP-ribose, the incorporation of P32-labelled NADH, and by cellular NADH. EGFR-ERK signaling was manipulated through ligand activation or signal interruption using the tyrphostin AG1478, or MEK inhibitor PD 184352. EGF activation of ERK prior to irradiation was associated with a marked increase in PARP activation and decreased survival in both cell lines. Prior inactivation of PARP protected both cell lines from the initial decrease in NAD+ and improved the survival of LNCaP cells following combined EGF and IR treatment. MEK inhibitor PD 184352 also reduced PARP activation and improved LNCaP survival following EGF and IR treatment. These data imply that PARP activation following exposure to ionizing radiation is enhanced through EGFR-ERK signaling.
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PMID:Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. 1729 9

Cinnamaldehyde (Cin) has been shown to be effective in inducing apoptotic cell death in a number of human cancer cells. The aim of this study was to investigate the effect of pifithrin-alpha (PFTalpha; a specific p53 inhibitor) and mitogen-activated protein kinases (MAPKs) inhibitors [namely SP600125 (a specific JNK inhibitor), SB203580 (a specific p38 inhibitor) and PD98059 (a specific ERK inhibitor)] on apoptotic signaling transduction mechanism induced by Cin in human hepatoma PLC/PRF/5 (CD95-negative) cells. Using XTT assay, Cin exhibited a powerful cytotoxic effect and apoptotic induction in PLC/PRF/5 cells. Apoptosis was elicited when cells were treated with 1 microM Cin as characterized by morphological changes and the appearance of phosphatidylserine on the outer surface of the plasma membrane. Cin down-regulated the expression of Bcl-(XL), up-regulated mutant p53 and Bax proteins and promoted caspase-3 to active forms, as well as cleaving poly (ADP-ribose) polymerase (PARP) in a time-dependent pattern. This could be supported by the activation and phosphorylation of MAPKs, including JNK, ERK and p38 kinases. Pre-incubation with PFTalpha and specific MAPK inhibitors significantly diminished the effect of Cin-induced apoptosis. The activities of anti-apoptotic (Bcl-(XL)) and pro-apoptotic (Bax) proteins were remarkably affected by PFTalpha and PD98059 pre-treatment. PFTalpha effectively blocked PARP cleavage in cells treated with Cin, and also markedly prevented the phosphorylation of JNK, p38 and ERK proteins. These results suggest that p53 induction and MAPK signaling pathways are required for Cin-mediated apoptosis in PLC/PRF/5 cells.
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PMID:MAPK inhibitors and pifithrin-alpha block cinnamaldehyde-induced apoptosis in human PLC/PRF/5 cells. 1767 46

CD54 is a cell surface adhesive glycoprotein, which is expressed in most cells. Interaction between CD54 and its ligands is involved in several cellular events including activation, proliferation, and cell death and also cell-to-cell adhesion. In the present study, we found that cross-linking of CD54 on Burkitt lymphoma cell lines, Raji and Ramos, induced apoptosis. We investigated that cross-linking of CD54 on Raji and Ramos using immobilized anti-CD54 mAb (clone 6.5B5) leads to apoptosis. CD54-induced apoptosis took place in association with an increase of intracellular reactive oxygen species (ROS) and a loss of the mitochondrial membrane potential and also the activation of caspases 3 and 9, resulting in the degradation of the proteolytic poly (ADP-ribose) polymerase. Pretreatment of each N-acetyl cystein and N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (a broad caspase inhibitor) blocked apoptosis. Cross-linking of CD54 immediately induced expression of fasL, which was inhibited by pretreatment of N-acetyl cystein. NOK-1 (antagonistic anti-fasL), ZB4 (antagonistic anti-fas), and N-benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketon (caspase 8 inhibitor) effectively rescued cells from apoptosis via adjacent fas-fasL interaction but did not block ROS generation. Taken together, it is concluded that engagement of CD54 on B lymphoma cell lines by anti-CD54 mAb may trigger fasL expression through ROS generation and may subsequently induce apoptosis in adjacent fas-fasL interaction.
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PMID:Cross-linking of CD54 on Burkitt lymphoma cell line Raji and Ramos induces FasL expression by reactive oxygen species and apoptosis of adjacent cells in Fas/FasL interaction. 1789 65


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