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)

Basic transcription factor 3 (BTF3) acts as a transcription factor and modulator of apoptosis, and is differentially expressed in colorectal cancer and glioblastomas. In the present study, the expression of BTF3, as well as its role in apoptosis and gene transcription, was analyzed in pancreatic ductal adenocarcinoma (PDAC). QRT-PCR, immunohistochemistry, immunoblotting, and immunofluorescence analyses were carried out to investigate BTF3 mRNA/protein expression and localization. BTF3 silencing in pancreatic cancer cells was performed using specific siRNA molecules. Functional analyses were carried out using cell growth assays, apoptosis assays, and DNA array analysis. BTF3 and BTF3a exhibited 1.3-fold and 4.6-fold increased median mRNA levels in PDAC tissues, compared to normal pancreatic tissues. BTF3 localized mainly in the cytoplasm and nuclei of tubular complexes and pancreatic cancer cells. Pancreatic cancer cell lines expressed the mRNA and protein of BTF3a (27 kDa) and BTF3b (22 kDa) isoforms. BTF3 silencing using specific siRNA molecules did not influence apoptosis induced by chemotherapy or radiotherapy. In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.
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PMID:Basic transcription factor 3 (BTF3) regulates transcription of tumor-associated genes in pancreatic cancer cells. 1731 87

In this paper, adsorption of lysozyme onto two kinds of mesoporous adsorbents (KIT-5 and AISBA-15) has been investigated and the results on the effects of pore geometry and stability of the adsorbents are also discussed. The KIT-5 mesoporous silica materials possess cage-type pore geometry while the AISBA-15 adsorbent has mesopores of cylindrical type with rather large diameter (9.7 nm). Adsorption of lysozyme onto AISBA-15 aluminosilicate obeys a Langmuir isotherm, resulting in pore occupation of 25 to 30%. In contrast, the KIT-5 adsorbents showed very small adsorption capacities for the lysozyme adsorption, typically falling in 6 to 13% of pore occupation. The cage-type KIT-5 adsorbents have narrow channel (4 to 6 nm) where penetration of the lysozyme (3 x 3 x 4.5 nm) might be restricted. The KIT-5 adsorbent tends to collapse after long-time immersion in water, as indicated by XRD patterns, while the AISBA-15 adsorbent retains its regular structure even after immersion in basic water for 4 days. These facts confirm superiority of the AISBA-15 as an adsorbent as compared with the KIT-5 mesoporous silicates. This research strikingly demonstrates the selection of mesoporous materials is crucial to achieve efficient immobilization of biomaterials in aqueous environment.
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PMID:Lysozyme adsorption onto mesoporous materials: effect of pore geometry and stability of adsorbents. 1745 Aug 41

Obesity is an epidemic disease that may affect brain function. The present study examined the effect of high fat diet (HF) and physical exercise on peripheral tissue and hippocampal signaling. CF-1 mice (n = 4, per cage) were divided into groups receiving high fat (HF) or control (CD) diets for 5 months, with or without voluntary exercise. Serum triacylglycerol, total cholesterol, HDLc, liver triacylglycerol and glycogen concentrations were evaluated (n = 6). Also, the phosphorylation state of the AKT --> ERK 1/2 --> CREB pathway (AKT, pAKTser473, ERK 1/2, pERK 1/2, CREB and pCREB, n = 4-6) was analyzed in the hippocampus. HF diet caused an increase in AKT phosphorylation at ser473 (P < 0.05), while exercise increased the phosphorylation of ERK 1/2 (P < 0.05) and CREB (P < 0.05). As expected, exercise reversed some of the harmful effects of HF, i.e., increased liver deposition of fat (P < 0.05) and fat gain in the abdominal region (P < 0.05). In conclusion, the effects of exercise and HF diet on brain signaling appear to affect the hippocampal AKT --> ERK 1/2 --> CREB pathway in independent ways: HF intake caused increased phosphorylation of AKTser473, while exercise increased ERK 1/2 --> CREB signaling. The physiological relevance of these findings in brain function remains to be elucidated.
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PMID:Different effect of high fat diet and physical exercise in the hippocampal signaling. 1803 3

To determine ancestral allele in possible cancer-associated polymorphisms, DNA samples from 10 chimpanzees (Pan troglodytes) were sequenced for alleles corresponding to 17 polymorphisms: 8 short tandem repeats [IL1RN (alias IL-1RA) variable number tandem repeat (VNTR); TYMS (previously TS) VNTR; AR CAG repeat; dinucleotide repeats of UGT1A1, IGF1, IFNG (alias IFN-gamma), ESR1 (alias ER-alpha), and EGFR] and 9 single nucleotide polymorphisms (MMP1-1607 1G/2G, MMP3-1171 5A/6A, OGG1 Ser326Cys, ALDH2 Gly487Lys, TP53 Arg72Pro, ABCG2 Gln141Lys, MGMT Leu84Phe, SOD2 Ala-9Val, and MTHFR Ala222Val). No chimpanzee polymorphism corresponded to human IL1RN VNTR; the ancestral allele was a repeat lost in humans. Dinucleotide repeat polymorphisms of IGF1, IFNG, ESR1, and EGFR were shared by chimpanzees, but the length of repeats tended to be longer in humans than in chimpanzees. This tendency was particularly evident for IGF1. All of the SNPs tested are human-specific nucleotide changes. The ancestral allele 7A was shown to be lost in MMP3-1171 5A/6A. Thus, all of the possible cancer-associated polymorphisms tested have human-specific alleles, and the ancestral allele is lost in three polymorphisms (IL1RN VNTR, UGT1A1 CA repeat, and MMP3-1171 5A/6A), suggesting a possible involvement of human-specific alleles in cancer susceptibility.
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PMID:Determination of ancestral allele for possible human cancer-associated polymorphisms. 1806 29

TLR4 (Toll-like receptor 4) and B7-H1, which were known to be restricted to immune cells in the past, were found to be aberrantly expressed in a majority of tumor cells, facilitating tumor evasion from immune surveillance. Our study demonstrated that activation of TLR4 signaling in bladder cancer cells up-regulated B7-H1 expression. Furthermore, this regulation was significantly attenuated by ERK or JNK inhibitor. Our results elucidated the molecule mechanism of regulation of B7-H1 expression through TLR4 signaling and may suggest new strategies of down-regulating the cancer-associated B7-H1 expression for bladder cancer treatment.
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PMID:TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells. 1860 6

Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity toward the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant manner, to change downstream signaling, differentially induce Mitogen-activated protein kinase (extracellular signaling-regulated kinase 1/2) signaling and associated cell proliferation and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific manner. Mutations of the conserved ion pair E884-R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity toward preclinical MET inhibitors SU11274 (unchanged) and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET and FAK) and tumor-suppressor gene (LKB1). Targeted therapy using small-molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.
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PMID:Disruption of the EGFR E884-R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity. 1901 41

The underlying mechanism by which anti-VEGF agents prolong cancer patient survival is poorly understood. We show that in a mouse tumor model, VEGF systemically impairs functions of multiple organs including those in the hematopoietic and endocrine systems, leading to early death. Anti-VEGF antibody, bevacizumab, and anti-VEGF receptor 2 (VEGFR-2), but not anti-VEGFR-1, reversed VEGF-induced cancer-associated systemic syndrome (CASS) and prevented death in tumor-bearing mice. Surprisingly, VEGFR2 blockage improved survival by rescuing mice from CASS without significantly compromising tumor growth, suggesting that "off-tumor" VEGF targets are more sensitive than the tumor vasculature to anti-VEGF drugs. Similarly, VEGF-induced CASS occurred in a spontaneous breast cancer mouse model overexpressing neu. Clinically, VEGF expression and CASS severity positively correlated in various human cancers. These findings define novel therapeutic targets of anti-VEGF agents and provide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs.
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PMID:Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome. 1901 93

This study explored the role of secreted fibroblast-derived factors in prostate cancer growth. Analyses of matched normal and tumor tissue revealed up-regulation of CXCL14 in cancer-associated fibroblasts of a majority of prostate cancer. Fibroblasts over-expressing CXCL14 promoted the growth of prostate cancer xenografts, and increased tumor angiogenesis and macrophage infiltration. Mechanistic studies demonstrated that autocrine CXCL14-stimulation of fibroblasts stimulate migration and ERK-dependent proliferation of fibroblasts. CXCL14-stimulation of monocyte migration was also demonstrated. Furthermore, CXCL14-producing fibroblasts, but not recombinant CXCL14, enhanced in vitro proliferation and migration of prostate cancer cells and in vivo angiogenesis. These studies thus identify CXCL14 as a novel autocrine stimulator of fibroblast growth and migration, with multi-modal tumor-stimulatory activities. In more general terms, our findings suggest autocrine stimulation of fibroblasts as a previously unrecognized mechanism for chemokine-mediated stimulation of tumor growth, and suggest a novel mechanism whereby cancer-associated fibroblasts achieve their pro-tumorigenic phenotype.
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PMID:CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. 1921 29

Epidemiological and molecular data suggest the involvement of estrogen signaling in colorectal tissue, mediated mainly through estrogen receptor beta (ERbeta). Estrogens may mediate their effects in epithelial cells indirectly by acting on stromal cells. Expression of ERalpha, ERbeta1, and the ER coregulators, amplified in breast cancer-1 (AIB-1) and transcriptional intermediary factor 2 (TIF-2), was evaluated in myofibroblasts of 107 colorectal carcinomas, 77 paired samples of normal mucosa, and 29 adenomas by immunohistochemistry. Double immunostaining with a-SMA was used to identify the myofibroblasts of normal tissue, adenomas, and cancer microenvironment. ERalpha was not expressed in stromal cells. Nuclear expression of ERbeta1, AIB-1, and TIF-2 in myofibroblasts gradually increased from normal mucosa, through adenomas, to carcinomas. Cytoplasmic ERbeta1 and TIF-2 expression was enhanced in carcinomas compared to normal mucosa and adenomas. Enhanced nuclear and cytoplasmic ERbeta1 expression and elevated nuclear AIB-1 expression were more frequently noted in myofibroblasts of carcinomas of advanced stage. ERbeta1 expression in cancer-associated myofibroblasts correlated to AIB-1 and TIF-2 expression. None of the markers correlated with patients' prognosis. Our findings imply that ERbeta1-dependent (genomic and non-genomic) and ER-coregulator-dependent (AIB-1, TIF-2) signal transductions in myofibroblasts may be involved in the initiation and progression of colorectal carcinomas.
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PMID:Estrogen signaling in colorectal carcinoma microenvironment: expression of ERbeta1, AIB-1, and TIF-2 is upregulated in cancer-associated myofibroblasts and correlates with disease progression. 1927 4

Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we show that birth defect and cancer-associated FGFR2 mutants promote DNA-damage signaling and p53-dependent senescence in primary mouse and human cells. Senescence promoted by FGFR mutants was associated with downregulation of c-Myc and forced expression of c-Myc facilitated senescence escape. Whereas c-Myc expression facilitated senescence bypass, mutant FGFR2 signaling suppressed c-Myc-dependent apoptosis and led to oncogenic transformation. Cells transformed by coexpression of a constitutively activated FGFR2 mutant plus c-Myc appeared to be become highly addicted to FGFR-dependent prosurvival activities, as small molecule inhibition of FGFR signaling resulted in robust p53-dependent apoptosis. Our data suggest that senescence-promoting activities of mutant FGFRs may normally limit their oncogenic potential and may be relevant to their ability to disrupt morphogenesis and cause birth defects. Our results also raise the possibility that cancers originating through a combination of constitutive FGFR activation and deregulated Myc expression may be particularly sensitive to small molecule inhibitors of FGF receptors.
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PMID:The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects. 1940 60


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