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)

Simultaneous deregulation of both Wnt and ErbB growth factors has previously been shown to result in the cooperative induction of mammary gland tumors. Using the murine mammary tumor virus (MMTV)-Wnt-1 transgenic model of mammary carcinoma, we have identified an unvarying association between beta-catenin and epidermal growth factor receptor/c-Neu (ErbB1/ErbB2) heterodimers in mammary gland tumors, indicating a requirement for ErbB signaling in Wnt-mediated tumorigenesis. Expansion of these observations to a second transgenic model, MMTV-c-Neu, demonstrated similar tumor-specific interactions, including an ErbB1 ligand-inducible phosphorylation of both beta-catenin and c-Neu. Direct relevance of these findings to human breast cancer was established upon examination of a set of human infiltrating ductal breast adenocarcinoma and lymph node metastasis tissues taken at surgery. These data revealed increased levels of beta-catenin in tumors and metastases versus normal breast as well as an association between beta-catenin and c-Neu that measurably occurs only in neoplasia, most strongly in metastatic lesions. These studies have identified a seemingly indispensable interaction between beta-catenin and epidermal growth factor receptor/c-Neu heterodimers in Wnt-1-mediated breast tumorigenesis that may indicate a fundamental signaling event in human metastatic progression.
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PMID:ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas. 1195 Aug 45

The relationship of thyroid transcription factor-1 (TTF-1) and HER2/neu expression in non-small cell lung cancer (NSCLC) with multiple parameters including survival were examined. Patients with primary NSCLC who had surgical resection and follow-up of at least 5 years were included in the study. There were 57 patients (38 men and 19 women), 44 to 75 years old (median age, 61 years); 28 patients had adenocarcinoma (AD) and 29 had squamous cell carcinoma. Tumors were examined for TTF-1 and HER2/neu expression using formalin-fixed, paraffin-embedded tissue. Clinical and follow-up data were obtained from the hospital records and Cancer Center database. Representative tumor sections were stained using standard immunohistochemical technique and commercial antibodies for TTF-1 (clone 8G7G3/1, Dako) and HER2/neu (polyclonal, Dako). Tumors were graded as negative (<5%), weak positive (5-49%), and strong positive (>50%), based on the percentage of positively stained tumor cells. Statistical analyses were performed using log-rank test, Pearson and Spearman correlations, and Kaplan-Meier survival curves. TTF-1 expression was seen in 45.6% of all tumors (80% of ADs and 14% of squamous cell carcinomas). Eighteen patients with tumors showing strong TTF-1 expression had significantly better survival compared with the 39 patients whose tumors showed negative or weak TTF-1 expression, although many more of the higher stage AD had strong TTF-1 staining than stage I AD. The TTF-1 expression did not correlate with tumor differentiation and was considered an independent predictor of survival. Seventeen of the 18 tumors with strong TTF-1 expression were ADs. Only eight of 57 (17%) tumors showed HER2/neu expression; seven of these eight were ADs. Although HER2/neu expression and survival did not show correlation, the majority of those ADs with weak or strong HER2/neu staining also had strong TTF-1 staining, were mostly stage I tumors. and had overall longer survival. All patients with stage I disease showed better 5-year survival compared with those with stages II and III. Hispanic patients had significantly worse survival compared with Caucasians and African Americans. The results of this study suggest that strong expression of TTF-1 is an independent predictor of better survival and may be a useful prognostic tool for evaluation of patients with NSCLC.
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PMID:Immunohistochemical study of thyroid transcription factor-1 and HER2/neu in non-small cell lung cancer: strong thyroid transcription factor-1 expression predicts better survival. 1205 26

The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure copy numbers of specific mRNAs using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and identify a profile of gene expression closely associated with angiogenesis. We measured a panel of nine potential angiogenesis markers from a mouse transgenic model of prostate adenocarcinoma (TRAMP) and a mouse skin model of vascular endothelial growth factor (VEGF)-driven angiogenesis. In both models, expression of VEGF correlated with expression of mRNAs encoding other angiogenic cytokines (angiopoietin-1 and angiopoietin-2), endothelial cell receptor tyrosine kinases (Flt-1, KDR, Tie-1), and endothelial cell adhesion molecules (VE-cadherin, PECAM-1). Relative to control, in dermis highly stimulated by VEGF, the Ang-2 mRNA transcript numbers increased 35-fold, PECAM-1 and VE-cadherin increased 10-fold, Tie-1 increased 8-fold, KDR and Flt-1 each increased 4-fold, and Ang-1 increased 2-fold. All transcript numbers were correspondingly reduced in skin with less VEGF expression, indicating a relationship of each of these seven markers with VEGF. Thus, this study identifies a highly efficient method for precise quantification of a panel of seven specific mRNAs that correlate with VEGF expression and VEGF-induced neovascularization, and it provides evidence that real-time quantitative RT-PCR offers a highly sensitive strategy for monitoring angiogenesis.
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PMID:Molecular profiling of angiogenesis markers. 1210 83

Methylsulfonyl (MeSO(2)) metabolites of polychlorinated biphenyls (PCBs) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethene (4,4'-DDE), itself a metabolite of the insecticide 4,4'-DDT, are emerging as a major class of contaminants in the tissues of wildlife and humans. We investigated the antiestrogenic capacity and potencies of 3'- and 4'-MeSO(2)-2,2',4,5,5'-pentachlorobiphenyl (CB101) and -2,2',4,5'-tetrachlorobiphenyl (CB49), which are among the most environmentally persistent MeSO(2)-PCBs, and 3-MeSO(2)-4,4'-DDE on estrogen receptor (ER)-dependent gene expression in four cell-based bioassay systems. Congener- and concentration-dependent antagonism of 17beta-estradiol (E2)-induced gene expression, rather than induction of ER-dependent gene expression, was observed for the MeSO(2)-PCBs on lucifierase activity in stably transfected human breast adenocarcinoma T47D cells (ER-CALUX) and vitellogenin (vtg) production in primary hepatocytes from male carp fish (Cyprinus carpio) (CARP-HEP/vtg). 4'-MeSO(2)-CB101 and -CB49 had the highest antagonistic potency (i.e., maximum inhibition of about 70%, LOECs of 1.0 microM and 2.5 microM), whereas 3'-MeSO(2)-CB101 and -CB49 were less antagonistic; the precursor CB101 and MeSO(2)-PCB analog MeSO(2)-2,5-dichlorobenzene had no effect. Relative to the 4-MeSO(2)-PCBs, tamoxifen (IC(50), 0.06 microM and 0.7 microM) was about 40 and 7 times more potent in the ER-CALUX and CARP-HEP/vtg assays, respectively. Congener- and concentration-dependent effects on aryl hydrocarbon receptor-mediated induction of EROD activity (carp hepatocytes), luciferase expression (H4IIE rat hepatoma [H4IIE.luc] cell line), or cell viability were not observed. 3-MeSO(2)-4,4'-DDE was neither estrogenic nor antiestrogenic in either of the bioassays. Inhibitory trends for the MeSO(2)-PCBs in a bioassay based on stably transfected human embryonic kidney cell (HEK293-ERalpha-ERE) were similar to the ER-CALUX and CARP-HEP/vtg bioassays, whereas the antagonism was weaker in a related HEK293-ERbeta-ERE bioassay. Our findings suggest that the 4'-MeSO(2)-PCBs are antiestrogenic in vitro via a reversible or surmountable interaction with fish or human ER, and that the interaction with human ERalpha is apparently favored over ERbeta. MeSO(2)-PCB metabolites are persistent and bioaccumulative contaminants, and therefore, could be potentially active as environmental antiestrogens in wildlife and humans.
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PMID:In vitro antiestrogenic effects of aryl methyl sulfone metabolites of polychlorinated biphenyls and 2,2-bis(4-chlorophenyl)-1,1-dichloroethene on 17beta-estradiol-induced gene expression in several bioassay systems. 1237 85

Src is a non-receptor protein tyrosine kinase, the expression and activity of which is increased in >80% of human colon cancers with respect to normal colonic epithelium. Previous studies from this and other laboratories have demonstrated that Src activity contributes to tumorigenicity of established colon adenocarcinoma cell lines. Src participates in the regulation of many signal transduction pathways, among which are those leading to cellular survival. In this study, we addressed the potential role of Src activation to a specific aspect of tumor cell survival, resistance to detachment-induced apoptosis (anoikis). Using five colon tumor cell lines with different biologic properties and genetic alterations, we demonstrate that expression and activity of Src corresponds with resistance to anoikis. Enforced expression of activated Src in subclones of SW480 cells (of low intrinsic Src expression and activity) increases resistance to anoikis; whereas decreased Src expression in HT29 cells (of high Src expression and activity) by transfection with anti-sense Src expression vectors increases susceptibility to anoikis. In contrast, increasing or decreasing Src expression had no effect on susceptibility to staurosporine-induced apoptosis in attached cells. PD173955, a Src family-specific tyrosine kinase inhibitor, increases the susceptibility of HT29 cells to anoikis in a dose- and time-dependent manner. Increasing Src expression and activity led to increased phosphorylation of Akt, a mediator of cellular survival pathways, whereas decreasing Src activity led to decreased Akt phosphorylation. In colon tumor cells with high Src activity, the PI3 kinase inhibitor LY 294002 sensitized cells to anoikis. These results suggest that Src activation may contribute to colon tumor progression and metastasis in part by activating Akt-mediated survival pathways that decrease sensitivity of detached cells to anoikis.
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PMID:Src activation regulates anoikis in human colon tumor cell lines. 1242 Feb 16

The sphingolipid metabolite, sphingosine-1-phosphate (S1P), formed by phosphorylation of sphingosine, has been implicated in cell growth, suppression of apoptosis, and angiogenesis. In this study, we have examined the contribution of intracellular S1P to tumorigenesis of breast adenocarcinoma MCF-7 cells. Enforced expression of sphingosine kinase type 1 (SPHK1) increased S1P levels and blocked MCF-7 cell death induced by anti-cancer drugs, sphingosine, and TNF-alpha. SPHK1 also conferred a growth advantage, as determined by proliferation and growth in soft agar, which was estrogen dependent. While both ERK and Akt have been implicated in MCF-7 cell growth, SPHK1 stimulated ERK1/2 but had no effect on Akt. Surprisingly, parental growth of MCF-7 cells was only weakly stimulated by S1P or dihydro-S1P, ligands for the S1P receptors which usually mediate growth effects. When injected into mammary fat pads of ovariectomized nude mice implanted with estrogen pellets, MCF-7/SPHK1 cells formed more and larger tumors than vector transfectants with higher microvessel density in their periphery. Collectively, our results suggest that SPHK1 may play an important role in breast cancer progression by regulating tumor cell growth and survival.
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PMID:Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. 1244 Nov 35

The HER2 oncogene, which encodes the tyrosine kinase receptor, is commonly overexpressed in several types of cancer. Treatment using a humanized monoclonal antibody bound to HER2 product is becoming standard therapy for advanced breast cancer. Overexpression occurs in approximately 30% of non-small cell lung cancers (NSCLCs) and has been associated with poor prognosis. However, the frequency of a genetic aberration in the HER2 gene in lung cancer and the association between gene amplification and prognosis are poorly defined. To clarify these relationships, we simultaneously analyzed protein overexpression by immunohistochemistry (IHC) and determined the gene copy number by FISH in 50 surgical specimens of NSCLC. A low-grade increase in the copy number (3 to 8 copies) of the HER2 gene was detected in 44% of tumors. Most represented polysomy of chromosome 17. Protein overexpression was observed in 26%. Overexpression was detected in adenocarcinoma more frequently than in squamous cell carcinoma. No significant correlation was observed between copy number increase and overexpression. Neither gene copy number increase nor overexpression correlated with survival. We conclude that the significance of HER2 status in NSCLC is different from that in breast cancer because high-grade amplification occurs rarely.
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PMID:Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer. 1245 54

Ovarian clear cell adenocarcinoma (CCA) is generally chemo-resistant. Recently the poor prognosis and resistance to chemotherapeutic agents of HER2/neu over-expressing tumors have become clear. Thus, we investigated the expression level of HER2 in surgically resected CCA and ovarian serous adenocarcinoma, endometrioid adenocarcinoma, and mucinous adenocarcinoma specimens, as well as CCA cell lines, by an immunohistochemical method. HER2 was over-expressed in 42.9% of CCA (P=0.026, vs. ovarian serous adenocarcinoma), 20.8% of ovarian serous adenocarcinoma, 23.1% of ovarian endometrioid adenocarcinoma, and 30.0% of mucinous adenocarcinoma specimens. Three CCA cell lines, RMG-1, HAC-II and KK were also positively stained for HER2. A flow-cytometric study of HER2 revealed 7.2-, 6.4- and 4.5-fold greater expression of HER2 than that of normal mammary gland, respectively. Trastuzumab, a humanized recombinant monoclonal antibody against HER2 significantly and dose-dependently reduced the growth of CCA cell lines in vitro. The extent of the inhibitory effect of trastuzumab was dependent on the expression level of HER2. Trastuzumab also dose-dependently inhibited the growth of xenografted RMG-1 tumor. The survival period of trastuzumab-treated mice was longer than that of the control group. From these findings, trastuzumab appears to be a candidate as a treatment modality for HER2 over-expressing ovarian CCA.
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PMID:HER2 is frequently over-expressed in ovarian clear cell adenocarcinoma: possible novel treatment modality using recombinant monoclonal antibody against HER2, trastuzumab. 1246 Apr 67

Mitogen-activated protein kinases (MAP kinases) play a key role in the regulation of cell survival and death. Effects of Treponema denticola ATCC 35405 on ERK, p38 and JNK MAP kinases, and cell behavior was studied using non-keratinizing periodontal ligament epithelial cells (PLE) in vitro. Compared to Chinese hamster ovary cells, human cervix adenocarcinoma cells, human osteosacroma cells and human gingival fibroblasts, PLE cells were much more resistant to T. denticola-induced reduction in cell viability, assayed by tetrazolium and crystal violet assays. A low dose of 5 x 10(7) T. denticola cells/ml increased DNA synthesis ([3H]thymidine uptake) in PLE cells but at higher concentrations DNA synthesis was decreased. TUNEL staining analysis showed that about 50% of epithelial cells in onolayers died through apoptosis when exposed to a high dose of 10(11) T. denticola/ml for 24 h. Morphological light and electron microscopic analysis supported the idea that both apoptotic and necrotic cell death took place. Rounding, membrane damage, fragmentation and detachment were observed in selective cells of both mono- and multilayered PLE cultures challenged with T. denticola. Western blot analysis using MAP kinase phosphospecific antibodies showed that T. denticola strongly but transiently activated ERK1 and ERK2, signals mediating cell proliferation, and JNK and p38, kinases mediating apoptosis. While a specific inhibitor of the ERK MAP kinase pathway prevented the T. denticola stimulation of cell proliferation, inhibitor of p38 increased the cell numbers in T. denticola-treated cultures. The results suggest that T. denticola activates epithelial cell MAP kinase signal pathways controlling cell proliferation and cell survival. In addition, T. denticola exerts cytotoxic effects that appear to predominate at higher bacterial concentrations.
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PMID:Treponema denticola may stimulate both epithelial proliferation and apoptosis through MAP kinase signal pathways. 1247 39

To investigate the role of ATP in ovarian tumorigenesis, the present study examined the expression of the P2U purinoceptor (P2U-R) and effect of ATP on growth stimulation in pre-neoplastic and neoplastic ovarian surface epithelial (OSE) cells. The immortalized OSE (IOSE) cell lines, including IOSE-29 (pre-neoplastic), IOSE-29EC (neoplastic), and OVCAR-3 (ovarian adenocarcinoma cell line) were used. Our results indicated that P2U-R mRNA was expressed and that ATP exerted a growth-stimulatory effect in IOSE-29, IOSE-29EC, and OVCAR-3. To investigate the mechanism of the growth-stimulatory effect, the activation of mitogen-activated protein kinases (MAPKs) by ATP was examined. Treatment with ATP resulted in MAPK activation in IOSE-29 and IOSE-29EC cells, whereas the stimulatory effect of ATP in cellular proliferation and MAPK activation was completely abolished in the presence of PD98059 (an MAPK/ERK kinase inhibitor) and staurosporin (a protein kinase C inhibitor), suggesting that the growth stimulatory effect of ATP is mediated via protein kinase C-dependent MAPK activation in pre-neoplastic and neoplastic OSE cells. In a time-dependent study, ATP significantly increased MAPK activity at 5-20 min in IOSE-29 cells. Activated MAPK declined to control levels after 20 min in these cells. Treatment with ATP significantly induced MAPK activation after 5 min and was sustained for 60 min in IOSE-29EC cells. In addition, treatment with ATP resulted in substantial phosphorylation of Elk-1, the Ets family transcriptional factor, confirming that ATP action is mediated by activation of MAPK. In conclusion, we have demonstrated that P2U-R was expressed and that ATP induced growth stimulation in IOSE and OVCAR-3 cells. Furthermore, treatment with ATP resulted in the activation of an MAPK cascade and phosphorylation of Elk-1 in IOSE-29 and IOSE-29EC cells. These results suggest that the MAPK cascade may be involved in growth stimulation in response to ATP in pre-neoplastic and neoplastic OSE cells.
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PMID:Adenosine triphosphate activates mitogen-activated protein kinase in pre-neoplastic and neoplastic ovarian surface epithelial cells. 1249 27


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