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)

Telomerase is a regulated enzyme and its activity is tightly associated with cell proliferation. The mechanisms of this association are unclear, but specific growth factors may regulate telomerase activity. The present study examines the effect of epidermal growth factor (EGF) on telomerase activity and identifies the signal transduction pathway involved in this process. EGF up-regulated telomerase activity in EGF receptor-positive cells after the activation of telomerase reverse transcriptase (TERT) mRNA expression. This activation was rapid, peaked after 6 or 12 h and was not blocked by the concurrent exposure to cycloheximide, suggesting a direct effect of EGF on TERT transcription. Transient expression assays revealed that EGF activates the hTERT promoter and that the proximal core promoter is responsible for this regulation. The activation of hTERT mRNA expression by EGF was specifically blocked by MEK inhibitor, and in vitro kinase assays demonstrated that ERK is activated in response to EGF. Transient expression assays using mutant reporter plasmids revealed that an ETS motif located in the core promoter of hTERT is required for the EGF-induced transactivation of hTERT. Overexpression of wild type Ets in cells enhanced the EGF effect on hTERT transcription, while that of dominant negative Ets significantly repressed EGF action. These findings suggest that EGF activates telomerase through the direct activation of TERT transcription, in which the Ras/MEK/ERK pathway and Ets factor play major roles. Our data support the notion that growth factors directly regulate telomerase via specific signal transduction pathways.
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PMID:Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway. 1203 63

One hallmark of tumor formation is the transcriptional upregulation of human telomerase reverse transcriptase, hTERT, and the resultant induction of telomerase activity. However, little is presently understood about how hTERT is differentially activated in tumor cells versus normal somatic cells. Specifically, it is unclear if oncoproteins can directly elicit hTERT expression. To this end, we now show that three oncoproteins, HER2/Neu, Ras, and Raf, stimulate hTERT promoter activity via the ETS transcription factor ER81 and ERK mitogen-activated protein (MAP) kinases. Mutating ER81 binding sites in the hTERT promoter or suppression of ERK MAP kinase-dependent phosphorylation of ER81 rendered the hTERT promoter unresponsive to HER2/Neu. Further, expression of dominant-negative ER81 or inhibition of HER2/Neu significantly attenuated telomerase activity in HER2/Neu-overexpressing SKBR3 breast cancer cells. Moreover, HER2/Neu, Ras, and Raf collaborated with ER81 to enhance endogenous hTERT gene transcription and telomerase activity in hTERT-negative, nonimmortalized BJ foreskin fibroblasts. Accordingly, hTERT expression was increased in HER2/Neu-positive breast tumors and breast tumor cell lines relative to their HER2/Neu-negative counterparts. Collectively, our data elucidated a mechanism whereby three prominent oncoproteins, HER2/Neu, Ras, and Raf, may facilitate tumor formation by inducing hTERT expression in nonimmortalized cells via the transcription factor ER81.
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PMID:Upregulation of the Catalytic Telomerase Subunit by the Transcription Factor ER81 and Oncogenic HER2/Neu, Ras, or Raf. 1467 40

Telomerase is expressed in many human cancers and cell lines and is thought to contribute to their immortality. To date, little is known about the expression of telomerase in nonepithelial tumors. The objective of this study was to evaluate the expression of human telomerase reverse transcriptase (hTERT) in gastrointestinal stromal tumors (GISTs). Twenty-three GISTs (9 low malignant potential, 10 primary malignant, and 4 intra-abdominal recurrences) were evaluated for hTERT expression by using immunohistochemistry on tissue microarray. Tissue blocks were retrieved, and hematoxylin and eosin stains were performed to evaluate the histological tumor type. All cases were strongly positive for KIT (CD117). Immunohistochemistry for hTERT was performed. Eight of 9 cases of the low malignant potential group were negative for hTERT immunoexpression, whereas all malignant GISTs showed positive staining that varied from weak to strong immunoreactivity. Six of 10 cases of the primary malignant GISTs were strongly positive for hTERT. The remaining cases (4/10) showed weak staining. All recurrent GISTs (4/4) showed strong positive immunostaining for hTERT. One malignant case was weakly positive for hTERT, but its recurrence was strongly positive. These results suggest that hTERT expression occurs preferentially in malignant tumors and that telomerase activity may occur during the progression of GISTs. Immunohistochemical staining for hTERT may be a useful marker for the prognostication of GISTs.
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PMID:Expression of human telomerase reverse transcriptase in gastrointestinal stromal tumors occurs preferentially in malignant neoplasms. 1549 90

Telomerase is a specialized reverse transcriptase that extends telomeres of eukaryotic chromosomes. The functional telomerase complex contains a telomerase reverse transcriptase catalytic subunit and a telomerase template RNA. We have previously demonstrated that human telomerase reverse transcriptase (hTERT) catalytic subunit is functionally compatible with a telomerase template RNA from rabbit. In this study, we show that hTERT is also functionally compatible with a telomerase template RNA from bovine. Introduction of hTERT into bovine lens epithelial cells (BLECs) provides the transfected cells telomerase activity. The expressed hTERT in BLECs supports normal growth of the transfected cells for 108 population doublings so far, and these cells are still extremely healthy in both morphology and growth. In contrast, the vector-transfected cells display growth crisis after 20 population doublings. These cells run into cellular senescence due to shortening of the telomeres and also commit differentiation as indicated by the accumulation of the differentiation markers, beta-crystallin and filensin. hTERT prevents the occurrence of both events. By synthesizing new telomere, hTERT prevents replicative senescence, and through regulation of MEK/ERK, protein kinase C, and protein kinase A and eventual suppression of the MEK/ERK signaling pathway, hTERT inhibits differentiation of BLECs. Our finding that hTERT can suppress RAS/RAF/MEK/ERK signaling pathway to prevent differentiation provides a novel mechanism to explain how hTERT regulates cell differentiation.
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PMID:Human telomerase reverse transcriptase immortalizes bovine lens epithelial cells and suppresses differentiation through regulation of the ERK signaling pathway. 1584 92

The characterization of tumor antigens recognized by immune effector cells has opened the perspective of developing therapeutic vaccines in the field of breast cancer. The potential advantages of the vaccines are: (i) the induction of a robust immune response against tumors that are spontaneously weekly immunogenic; (ii) the tumor specificity for some antigens; (iii) the good tolerance and safety profile and (iv) the long-term immune memory, critical to prevent efficiently tumor recurrence. Most trials evaluating breast cancer vaccines have been carried out in patients with extended metastatic breast cancer, characterized by aggressive tumors, resistant to standard cytotoxic treatments, so that clinical efficacy was difficult to achieve. However, some significant immune responses against tumor antigens induced upon vaccinations were recorded. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. Data of clinical activity have been observed by using vaccines targeting HER2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen and carbohydrate antigen given after stem cell rescue. The review discusses possible future directions for vaccine development and applications in the adjuvant setting.
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PMID:Breast cancer vaccines: a clinical reality or fairy tale? 1629 74

Tissue stem cells may serve as progenitors for malignant tumors derived from the same tissue. Here, we report the establishment of immortalized human mesenchymal stem cells (ihMSC) and tested the feasibility of using ihMSC as presarcomatous cells. Immortalization was achieved by introducing the genes for human telomerase reverse transcriptase and Bmi1. ihMSC retained the potential for multi-directional differentiation of the original MSC. To transform ihMSC, we introduced an oncogenic H-ras(Val12) gene, and established the cell line ihMSC-ras. ihMSC-ras had the phenotype of fully transformed cells and retained adipogenic and chondrogenic, but not osteogenic, potential. Interestingly, ihMSC-ras demonstrated morphological features of autophagy, and inhibition of the ERK pathway suppressed the production of autophagosomes, indicating that ras/ERK signaling is responsible for the induction of autophagy. Thus ihMSC will serve as a material with which to analyze the tumorigenic and differentiation-modifying effects of candidate oncogenes involved in the development of sarcomas.
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PMID:In vitro transformation of mesenchymal stem cells by oncogenic H-rasVal12. 1717 60

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Tumor specific cellular and humoral immunotherapy may be a viable approach for the treatment of HCC. This study investigated specific inhibitory and cytotoxic effects on hepatocellular carcinoma (HCC) induced by the peptide, designated HBc Delta-5L, using HBc carrier with multiple T cell and B cell sequence insertions. We developed the HBc Delta carrier containing insertions of multiple CTL and T helper (Th) epitopes, which were selected from HCC tumor associated antigens (TAAs) including alpha fetoprotein (AFP), melanoma antigen gene (MAGE) and telomerase reverse transcriptase (TERT) antigen, and ligands for EGFR and IGFR, designated HBc Delta-5L. LDH release assay and IFN-gamma ELISPOT assay were carried to determine whether HBc Delta-5L could induce specific cytotoxicity in peripheral blood mononuclear cells (PBMC) of HCC donors. The levels of antibodies and inhibitory effects of sera of immunized mice against HBc Delta-5L were also identified. LDH release assay revealed that PBMC from HCC donor group (n=8) stimulated with HBc Delta-5L could specifically kill target tumor cells and specific lysis was 62.7% (E:T=60:1). ELISPOT assay showed a significant increase in secretion of IFN-gamma from PBMC of HCC donor group in response to HBc Delta-5L. Further, high specific antibody titers were elicited in immunized mice and revealed 42% inhibition of cell growth. These results indicated that inhibitory and cytotoxic effects could be efficiently induced by HBc Delta-5L recombinant particles using HBc Delta as carrier and suggested that it could be important in design of immunotherapeutic approaches.
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PMID:Anti-tumor effects of immunotherapeutic peptide on the treatment of hepatocellular carcinoma with HBc carrier. 1754 80

Telomerase maintains telomeres to preclude cell senescence. It remains elusive how telomerase activity is repressed in differentiated cells, but retained at high levels in stem cells and cancer. Recent studies suggest that the Ets transcription factor family, downstream of the mitogen signaling pathways of MAP kinase, regulates telomerase activity at the gene transcription level of human telomerase reverse transcriptase (hTERT). Several Ets transcription factors are involved in regulating hTERT gene expression, both directly and indirectly through the proto-oncogene c-myc. ER81 may mediate telomerase activation in telomerase-negative fibroblasts stimulated by oncogenes Her2/Neu, Ras, and Raf. Ets2 may also play an important role in regulating the hTERT gene; but further studies are required to decipher the mechanisms in the regulation of telomerase activity.
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PMID:Transcriptional regulation of telomerase activity: roles of the the Ets transcription factor family. 1798 75

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

Gastrointestinal stromal tumors (GIST) are rare in the vermiform appendix. Only 5 cases have been reported so far, all being 14 mm or less, and they have yet not been investigated at the molecular level. Here, we report 2 appendiceal gastrointestinal stromal tumors in a 78-year-old woman and a 72-year-old man with a history of endometrial adenocarcinoma and urinary bladder carcinoma, respectively. The first patient had a history of pelvic irradiation. Both gastrointestinal stromal tumors were incidental findings at surgery for appendicitis-like symptoms and on follow-up for bladder carcinoma, respectively. Tumors were 5 and 25 mm and were located in the mid portion and the tip, respectively. The larger gastrointestinal stromal tumor was pedunculated. Both revealed a spindle cell histology with variable stromal hyalinization and occasional skeinoid fibers in 1 case. Immunohistochemistry showed reactivity for CD117 and CD34 and loss of p16 in both. Case 2 overexpressed the catalytic subunit of the human telomerase reverse transcriptase immunohistochemically. Molecular analysis of KIT revealed a missense mutation K558R in case 1 and an in-frame deletion I571_R588 in case 2, both in the juxtamembrane domain (exon 11). Comparative genomic hybridization was successful in case 2 (larger lesion) and revealed no chromosomal imbalance. We suggest that the molecular pathogenesis of appendiceal gastrointestinal stromal tumors beyond initiating KIT mutations might be different from their gastric and intestinal counterparts. The coincidence of loss of p16 and overexpression of human telomerase reverse transcriptase seems to be in contradiction to the small size, the benign nature, and the limited growth potential of appendiceal gastrointestinal stromal tumors.
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PMID:Gastrointestinal stromal tumors of the vermiform appendix: clinicopathologic, immunohistochemical, and molecular study of 2 cases with literature review. 1854 14


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