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)

While small molecule inhibitors of the phosphatidylinositide-3-kinase (PI3K) are expected to impact the development of new cancer therapy, the tumor types and underlying cellular pathways determining inhibitor response remain poorly defined. In this report, we have studied anti-proliferative effects of the PI3K inhibitors WAY-266176 and WAY-266175 in a panel of histologically diverse cancer cells. Inactivation of PI3K caused potent growth suppression in some cells (MDA468, BT549, MDA361, MCF7, LNCap, PC3MM2) but minimal suppression in others (MDA231, MDA435, DU145, HCT116, A549), which correlated with a differential down-regulation of cyclin D1, c-Myc, and induction of apoptosis. A heightened PI3K/AKT/mTOR signaling was linked to the sensitive phenotype but did not generally predict inhibitor response. Interestingly, the resistant cells all displayed an elevated phospho-ERK that remained elevated after serum deprivation. In HCT116 cells, activation mutations in the PI3K catalytic subunit PIK3CA and Ki-Ras correlated with a resistant phenotype, which was partially sensitized by homologous replacement with the wild-type Ki-Ras but not by deletion of cellular PTEN. Depletion of Mek1 via siRNA in resistant cells enhanced PI3K inhibitor-induced growth suppression. Moreover, a profoundly augmented growth suppression and apoptosis were achieved in resistant cells by combination treatment with WAY-266176/WAY-266175 and Mek1 kinase inhibitor CI-1040 or UO126. The combination therapy efficiently inhibited mitogenic signaling and reduced expression of cyclin D1 and c-Myc. Our results identify deregulation of the Ras/Raf/Mek/ERK pathway as a dominant determinant in cancer cell resistance to PI3K inhibitors and highlight combined targeting of PI3K and Mek1 as an effective anticancer strategy.
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PMID:Response and determinants of cancer cell susceptibility to PI3K inhibitors: combined targeting of PI3K and Mek1 as an effective anticancer strategy. 1834 31

The constitutively activated tyrosine kinase Fip1-like 1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRalpha) causes eosinophilic leukemia EoL-1 cells to proliferate. Recently, we demonstrated that histone deacetylase inhibitors suppressed this proliferation and induced the differentiation of EoL-1 cells into eosinophils in parallel with a decrease in the level of FIP1L1-PDGFRalpha. In this study, we analyzed the mechanism by which FIP1L1-PDGFRalpha induces the proliferation and whether the suppression of cell proliferation triggers the differentiation into eosinophils. The FIP1L1-PDGFRalpha inhibitor imatinib inhibited the proliferation of EoL-1 cells and decreased the level of the oncoprotein c-Myc as well as the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK). The proliferation of EoL-1 cells and expression of c-Myc were also inhibited by the MEK inhibitor U0126 and JNK inhibitor SP600125. The expression of the eosinophilic differentiation marker CCR3 was not induced by imatinib. These findings suggest that FIP1L1-PDGFRalpha induces the proliferation of EoL-1 cells through the induction of c-Myc expression via ERK and JNK signaling pathways, but is not involved in the inhibition of differentiation toward mature eosinophils.
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PMID:Mechanisms for the proliferation of eosinophilic leukemia cells by FIP1L1-PDGFRalpha. 1808 64

Ceramide 1-phosphate (C1P) was first shown to be mitogenic for fibroblasts, but the mechanisms whereby it stimulated cell proliferation have remained largely unknown. Here we demonstrate that C1P stimulates DNA synthesis and cell division in murine bone marrow-derived macrophages. C1P caused rapid phosphorylation of protein kinase B (PKB, also known as Akt), a downstream target of phosphatidylinositol 3-kinase (PI3-K). Selective inhibition of PI3-K blocked both DNA synthesis and cell growth. C1P induced phosphorylation of GSK-3beta, which is a major target of PKB, and this effect was also abolished by inhibition of PI3-K. In addition, C1P upregulated the expression of cyclin D1 and c-Myc, two major targets of GSK-3beta, which are important regulators of cell proliferation. C1P stimulated the activity of NF-kappaB, and inhibitors of this transcription factor completely blocked macrophage proliferation. Lastly, C1P induced phosphorylation of the mitogen activated protein kinases (MAPK) extracellularly regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK). Inhibition of ERK1/2 and JNK also blocked C1P-induced macrophage proliferation. It can be concluded that C1P stimulates macrophage proliferation through activation of the PI3-K/PKB, ERK and JNK pathways, and that GSK-3beta, c-Myc, cyclin D1, and NF-kappaB are important downstream effectors in this action.
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PMID:Ceramide 1-phosphate stimulates macrophage proliferation through activation of the PI3-kinase/PKB, JNK and ERK1/2 pathways. 1823 73

Non-small-cell lung cancer (NSCLC) is characterized by severe resistance to chemotherapy. Here, we demonstrate that A549 adenocarcinoma cells permanently differentiate with the antimetabolites methotrexate (MTX) and gemcitabine (GE) when blocking the resistance mechanism that normally counteracts this process. MTX (1-10 microM) and GE (1 microM) induced growth arrest accompanied by sustained extracellular signal-regulated kinase (ERK1/2) phosphorylation and moderate reduction of c-Myc levels after 96 h, whereas only a low percentage of the cells differentiated. Combination with the mitogen-activated protein kinase kinase (MEK) inhibitor 1,4-diamino-2,3-dicyano-1,4-bis-(methylthio)butadiene (U0126) reduced MTX- or GE-induced ERK1/2 over-phosphorylation, nearly abolished c-Myc expression, and provoked radical morphological changes in all cells. Besides the appearance of multilamellar bodies and intracellular cytokeratin reorganization, modulation of molecular markers occurred in a manner consistent with differentiation (gelsolin, +300%; surfactant protein A and C, -70%). Similar to U0126, c-Myc inactivation with specific small interfering RNA initiated differentiation only in the presence of MTX, demonstrating that inhibition of the mitogen-activated protein kinase/ERK pathway alone or down-regulation of c-Myc is not sufficient to induce this process. It is noteworthy that withdrawal of antitumoral drugs and U0126 neither reversed differentiation nor reactivated proliferation. Our results reveal that maintenance of a certain threshold of c-Myc expression through sustained ERK1/2 activation represents a molecular mechanism that confers resistance to antimetabolite-induced differentiation in A549 cells, and provide a novel molecular basis for therapeutic strategies based on irreversible differentiation of cancer cells using conventional chemotherapeutic antimetabolites in combination with inhibitors of the MEK/ERK pathway or c-Myc.
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PMID:Inhibition of c-Myc down-regulation by sustained extracellular signal-regulated kinase activation prevents the antimetabolite methotrexate- and gemcitabine-induced differentiation in non-small-cell lung cancer cells. 1835 95

Epidermal growth factor (EGF) promotes growth of normal ovarian surface as well as malignant ovarian epithelial cells. Further, EGF receptors are present on both normal and malignant ovarian surface epithelial cells and they are often constitutively activated in many cancers. Since telomerase confers cellular immortalization and survival through increased cellular proliferation, we sought to investigate the potential role of EGF to regulate telomerase activity in normal and ovarian cancer cells. While exogenous EGF failed to activate telomerase in normal ovarian surface epithelial cells, in cancer cells we herein report that: exogenous EGF activates telomerase activity and human telomerase reverse transcriptase gene (hTERT) transcription; EGF-induced telomerase activity is ERK 1/2-dependent; EGF targets Sp1 and c-Myc binding sites within the core region of the hTERT promoter; and proline-rich tyrosine kinase 2 (Pyk2) is a key mediator of EGF-mediated telomerase activity. Together, these data show that dysregulation of EGF signaling may promote cancer cell survival through up-regulation of telomerase activity.
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PMID:Pyk2/ERK 1/2 mediate Sp1- and c-Myc-dependent induction of telomerase activity by epidermal growth factor. 1836 74

Expression of specific proteins involved in regulation of cell proliferation and apoptosis was studied at the initial (7-8 days after tumor inoculation), median (13-14 days), and terminal (20-21 days) stages of murine NK/Ly lymphoma development. Western-blot analysis using antibodies to MEK-ERK signaling pathway, E2F-1/2 and c-Myc, pSTAT1, pSTAT3, pSTAT5, anti-apoptotic Bcl-XL and pro-apoptotic p53 and Rb proteins, as well as active cleaved forms of caspases-3, -6, -7, was carried out to investigate the growth and survival status of NK/Ly cells. There was a marked increase in the expression of E2F-1/2 transcription factors, MAPK signaling cascade and c-Myc, which suggests intensive proliferation of lymphoma cells at terminal stage of tumor development. However, cytomorphological investigation and electrophoretic study of DNA fragmentation have shown degeneration of NK/Ly lymphoma cells and increase in their death. No expression of p53 protein or cleaved forms of caspases-3, -6, -7 was found, which suggests a caspase-independent type of apoptosis in these cells. Ascitic fluid collected at a terminal stage of NK/Ly lymphoma development was significantly weaker in supporting tumor cell growth than ascitic fluid collected at the initial stage of tumor development. It is suggested that uncontrolled cell proliferation at terminal stage of the NK/Ly lymphoma development causes nutrient deprivation and deficiency of specific growth factors in the ascitic fluid, due to overexpression of MEK-ERK, E2F and c-Myc, thereby leading to the induction of apoptosis.
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PMID:Changes in signaling pathways of cell proliferation and apoptosis during NK/Ly lymphoma aging. 1859 74

New detection methods with prognostic power are needed for early identification of dysplasia and esophageal adenocarcinoma (EA) in patients with Barrett's esophagus (BE). This study assessed the relative sensitivity and specificity of conventional cytology, DNA ploidy analysis with digital image analysis (DIA), and fluorescence in situ hybridization (FISH) for the detection of dysplasia and adenocarcinoma in endoscopic brushing specimens from 92 patients undergoing endoscopic surveillance for BE. FISH used probes to 8q24 (C-MYC), 9p21 (P16), 17q12 (HER2), and 20q13. Four-quadrant biopsies taken every centimeter throughout visible Barrett's mucosa were used as the gold standard. The sensitivity of cytology, DIA, and FISH for low-grade dysplasia was 5%, 5%, and 50%, respectively; for high-grade dysplasia (HGD), 32%, 45%, and 82%, respectively; and for EA, 45%, 45%, and 100%, respectively. FISH was more sensitive (P < .05) than cytology and DIA for low-grade dysplasia, HGD, and EA. The specificity of cytology, DIA, and FISH among patients (n = 14) with tissue showing only benign squamous mucosa was 93%, 86%, and 100% (P = .22), respectively. All patients with a polysomic FISH result had HGD and/or EA within 6 months (n = 33). There was a significant difference between FISH categories (negative, 9p21 loss, gain of a single locus, and polysomy) for progression to HGD/EA (P < .001). These findings suggest that FISH has high sensitivity for the detection of dysplasia and EA in BE patients, with the power to stratify patients by FISH abnormality for progression to HGD/EA. Additional studies are needed to further evaluate the clinical use of FISH.
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PMID:A comparison of conventional cytology, DNA ploidy analysis, and fluorescence in situ hybridization for the detection of dysplasia and adenocarcinoma in patients with Barrett's esophagus. 1860 65

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract and is associated with mutations of the KIT or PDGFRA gene. In addition, other genetic events are believed to be involved in GIST tumorigenesis. Cytogenetic aberrations associated with these tumors thus far described include loss of 1p, 13q, 14q, or 15q, loss of heterozygosity of 22q, numeric chromosomal imbalances, and nuclear/mitochondrial microsatellite instability. Molecular genetic aberrations include loss of heterozygosity of p16(INK4A) and p14(ARF), methylation of p15(INK4B), homozygous loss of the Hox11L1 gene, and amplification of C-MYC, MDM2, EGFR1, and CCND1. GISTs in patients with neurofibromatosis type 1 appear to lack the KIT and PDGFRA mutations characteristic of GISTs and may have a different pathogenetic mechanism. Gene mutations of KIT or PDGFRA are critical in GISTs, because the aberrant versions not only are correlated with the specific cell morphology, histologic phenotype, metastasis, and prognosis, but also are the targets of therapy with imatinib and other agents. Furthermore, specific mutations in KIT and PDGFR appear to lead to differential drug sensitivity and may in the future guide selection of tyrosine kinase inhibitors. Activation of the receptor tyrosine kinases involves a signal transduction pathway whose components (mitogen-activated protein kinase, AKT, phosphoinositide 3-kinase, mammalian target of rapamycin, and RAS) are also possible targets of inhibition. A new paradigm of classification, integrating the standard clinical and pathological criteria with molecular aberrations, may permit personalized prognosis and treatment.
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PMID:Genetic aberrations of gastrointestinal stromal tumors. 1867 Dec 47

Herein, we show that both exogenously transfected and endogenously activated p53 repress promoter activity and expression of PDGFRB. p53 binds the proximal promoter containing the CCAAT motif as examined by EMSA and chromatin immunoprecipitation. However, gradual induction of p53 in tet-onSAOS2 cells resulted in a transient increase of the PDGFRB-promoter activity and its expression. As binding of p53 to the promoter increased, previously bound p73, DeltaNp73, c-Myc, HDAC1 and HDAC4 were dismissed from the repressed promoter, and p300 was recruited. The transient increase of the promoter activity was therefore induced by the release of the p73, Myc and HDACs, previously shown to act as repressors to this promoter. Along with further increase of p53, p300 was replaced by HDAC1 and HDAC4, resulting in decreased PDGFRB expression. For the repression, acetylation of the C-terminal lysines of p53 is important, and both acetyl-K373p53 and methyl-K370p53 became bound to the promoter. The acetyl-K373p53 was accumulated in the nucleus and colocalized with promyelocytic leukemia protein. Mitomycin treatment of MEF induced similar epigenetic modification of p53 and its binding to the promoter chromatin. Addition of a PDGFR tyrosine-kinase inhibitor to p53-inducing tet-onSAOS2 increased the number of apoptotic cells. These results suggest that p53 represses the PDGFRB promoter, facilitating the p53-induced apoptosis, whereas tumor cells with p53 mutation or a high level of DeltaNp73 or Myc could become refractory to the regulation.
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PMID:Kinetics of repression by modified p53 on the PDGF beta-receptor promoter. 1869 3

c-Myc drives uncontrolled cell proliferation in various human cancers. However, in mouse embryo fibroblasts (MEFs), c-Myc also induces apoptosis by activating the p19Arf tumor suppressor pathway. Tbx2, a transcriptional repressor of p19Arf, can collaborate with c-Myc by suppressing apoptosis. MEFs overexpressing c-Myc and Tbx2 are immortal but not transformed. We have performed an unbiased genetic screen, which identified 12 oncogenes that collaborate with c-Myc and Tbx2 to transform MEFs in vitro. One of them encodes the LPA2 receptor for the lipid growth factor lysophosphatidic acid (LPA). We find that LPA1 and LPA4, but not LPA3, can reproduce the transforming effect of LPA2. Using pharmacological inhibitors, we show that the in vitro cell transformation induced by LPA receptors is dependent on the Gi-linked ERK and PI3K signaling pathways. The transforming ability of LPA1, LPA2 and LPA4 was confirmed by tumor formation assays in vivo and correlated with prolonged ERK1/2 activation in response to LPA. Our results reveal a direct role for LPA receptor signaling in cell transformation and tumorigenesis in conjunction with c-Myc and reduced p19Arf expression.
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PMID:In vitro genetic screen identifies a cooperative role for LPA signaling and c-Myc in cell transformation. 1876 10


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