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)

The mechanism by which the ubiquitously expressed Src family kinases regulate mitogenesis is not well understood. Here we report that cytoplasmic tyrosine kinase c-Abl is an important effector of c-Src for PDGF- and serum-induced DNA synthesis. Inactivation of cytoplasmic c-Abl by the kinase-inactive Abl-PP-K(-) (AblP242E/P249E/K290M) or by microinjection of Abl neutralizing antibodies inhibited mitogenesis. The kinase-inactive SrcK295M induced a G(1) block that was overcome by the constitutively active Abl-PP (AblP242E/P249E). Conversely, the inhibitory effect of Abl-PP-K(-) was not compensated by Src. c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. Finally, we found that p53 inactivation and c-myc expression, two cell cycle events regulated by Src during mitogenesis, also implied c-Abl: c-Abl function was dispensable in cells deficient in active p53 and inhibition of c-Abl reduced mitogen-induced c-myc expression. These data identify a novel function of cytoplasmic c-Abl in the signalling pathways regulating growth factor-induced c-myc expression and we propose the existence of a tyrosine kinase signalling cascade (PDGFR/c-Src/c-Abl) important for mitogenesis.
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PMID:c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis. 1184

Cd(2+) exposure increases the risk of cancer in humans and animals. In this report, we have studied the effect of Cd(2+) on signal transduction and Ca(2+) mobilization in murine macrophages. At micromolar concentrations, Cd(2+) significantly increased cell division as judged by [3H]thymidine uptake and cell counts. Cd(2+)-treated cells continued to proliferate even after more than 4 weeks in culture. Cd(2+) (1 microM) treatment induced a 1.5- to 2-fold increase in cytosolic free Ca(2+), [Ca(2+)](i), which was transitory and/or oscillatory. The sources of this Ca(2+) included both inositol 1,4,5-trisphosphate (IP(3))-sensitive and -insensitive stores. Macrophage treatment with 1-(6-((17beta-3-methoxyestra-1,2,5(10)-triene-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), an inhibitor of phosphatidylinositol-specific phospholipase C (PLC), decreased Cd(2+)-induced formation of IP(3) in a concentration-dependent manner (K(d) about 2 microM). This caused a concomitant, partial decrease in the effect of Cd(2+) on [Ca(2+)](i). Cd(2+) itself crosses the macrophage membrane in part via L-type Ca(2+) channels, but it also interacts with a cell surface membrane protein(s) coupled to a pertussis toxin-sensitive G protein. Use of selective inhibitors of signal transduction and the quantitation of the levels of phosphorylated MAPK/ERK-activating kinase-1 (MEK1), extracellular signal-regulated kinase-1 (ERK1), and p38 mitogen-activated protein kinase (MAPK) suggests that the effects of Cd(2+) are mediated by the p21(ras)-dependent MAPK, but not the phosphoinositide 3 (PI 3)-kinase signalling pathway. The effect of activating these pathways includes increased availability of the transcription factor NFkappaB as well as activation of the early genes c-fos and c-myc.
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PMID:Cadmium-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. 1185 40

In 10 cases of Barrett adenocarcinoma, samples from 8 tumor areas (including superficial and deep from peripheral and central areas) and a regional lymph node metastasis were studied for amplification of c-myc, c-erbB-2, and EGFR. We analyzed loss of heterozygosity (LOH) at 3 loci (APC, MCC, and RB) and 2 anonymous microsatellite markers (D4S1652 and D18S474). We detected c-myc in variable fractions of tissue samples from 3 of 9 tumors; EGFR was amplified in 2 specimens from 1 tumor. One tumor demonstrated amplification of c-erbB-2 in all areas. LOH at the D4S1652, MCC, RB, APC, and D18S474 loci was found in 75% (3/4), 57% (4/7), 50% (4/8), 11% (1/9), and 0% (0/10) of informative cases, respectively. LOH generally was restricted to variable subpopulations of tumor cells within individual tumors. There was no obvious association of certain genetic alterations with topographically distinct tumor regions; however, superficial areas showed more frequent genetic alterations than areas from the deeply invading front. More aberrations were detected in the periphery than in the center. Barrett adenocarcinoma is characterized by marked intratumoral genetic heterogeneity, which must be considered when evaluating genetic alterations as indicators of response to therapy and prognosis.
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PMID:Intratumoral genetic heterogeneity in Barrett adenocarcinoma. 1193 30

Human oral squamous cell carcinoma cell lines (KOSCC-11, -25A, -25B, -25C, -25D, -25E, -33A, and -33B) were established by explantation culture from these oral squamous cell carcinomas. The histopathology of the primary tumors, in vitro growth characteristics, epithelial origin, in vitro anchorage-independency, in vivo tumorigenicity, the frequency of human papillomavirus (HPV) infections, and the status of proto-oncogenes, tumor suppressor genes, DNA mismatch repair genes, and microsatellite instability were investigated in the cell lines. KOSCC-11 is a well-differentiated oral squamous cell carcinoma (OSCC) derived from mandibular gingiva. KOSCC-25A, -25B, -25C, -25D, and -25E cell lines were derived from the same OSCC. KOSCC-33A and -33B were established from the same tumor that originated from the maxillary sinus. All tumor lines studied grew as monolayers and showed: i) epithelial origin by the presence of desmosome and keratin; ii) in vitro anchorage-independent growth ability; and iii) tumorigenic potential in nude mice. The cancer cell lines did not contain HPV DNA and did not express viral genes. Northern blot analysis revealed: i) overexpression of EGFR in four cell lines, ii) overexpression of c-H-ras in four cell lines, iii) overexpression of c-myc in three cell lines, iv) decreased expression of TGF-alpha in seven cell lines, and v) decreased expression of c-jun in five cancer cell lines compared with normal human oral keratinocytes. In all KOSCC cell lines and their corresponding tumor tissues, mutations were identified in highly-conserved functional regions of the p53 gene. The KOSCC-11 cell line contained a frameshift mutation and the other cell lines harbored an identical p53 mutation at codon 175 from CGC (Arg) to CTC (Leu). In five cell lines, a significant reduction of p21WAF1/Cip1 protein was evident. Cancer cell lines expressed higher level of Rb protein than normal human oral keratinocytes. DCC, a tumor suppressor gene, was not detected in KOSCC-25C. The KOSCC-33A cell line displayed microsatellite instability and showed a loss of hMSH2 expression. These well-characterized human OSCC cell lines should serve as useful tools for understanding the biological characteristics of oral cancer.
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PMID:Characterization of novel cell lines established from three human oral squamous cell carcinomas. 1201 92

Fluorescence in situ hybridization (FISH) is difficult to accomplish using thin-sections of paraffin-embedded lymphoid tissue because of the high cellularity and truncated cells that interfere with accurate scoring of individual nuclei. We modified and tested a new technique to isolate individual nuclei from tissue cores of paraffin-embedded tissue processed with xylene, proteinase K, citric acid, and pepsin. The efficacy of this method to study paraffin-embedded tissue was investigated in six normal lymph nodes or tonsils and 32 malignant lymphomas including five mantle cell, five follicular, five Burkitt, five extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue, five anaplastic large-cell, and seven diffuse large B-cell. Fusion of CCND1 and IgH, BCL2 and IgH, c-myc and IgH, and MALT1 and API2 were detected using probes with a dual-fusion FISH strategy. Anomalies involving ALK and BCL6 were detected using break-apart FISH probes. FISH studies were successful for each of the 38 specimens. Chromosome anomalies were detected in each malignant specimen, but not in the normal lymphoid tissue. The correct chromosome anomaly was detected in 22 of 22 specimens with genetic abnormalities that were established by other genetic techniques. This FISH technique is useful to detect chromosome anomalies with high sensitivity and specificity in paraffin-embedded tissue and may provide important diagnostic and prognostic genetic information.
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PMID:A new method to extract nuclei from paraffin-embedded tissue to study lymphomas using interphase fluorescence in situ hybridization. 1205 1

Clinical observations suggest that human breast tumors can adapt in response to endocrine therapy by developing hypersensitivity to estradiol. To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided evidence that long-term deprivation of estradiol causes adaptive hypersensitivity. The enhanced responses to estradiol do not involve mechanisms acting at the level of transcription of estrogen regulated genes. We found no evidence of hypersensitivity when examining the effects of estradiol on regulation of c-myc, pS2, progesterone receptor, several ER reporter genes or c-myb in hypersensitive cells. On the other hand, deprivation of breast cells long term was found to up-regulate a separate pathway whereby the estrogen receptor co-opts a classical growth factor pathway and induces rapid non-genomic effects. Through this pathway, estradiol caused rapid activation of mitogen-activated protein (MAP) kinase. In exploring the mechanisms mediating this event, we found that estradiol binds to cell membrane associated estrogen receptors and causes phosphorylation of Shc, an adaptor protein usually involved in growth factor signaling pathways. ERalpha was found to complex with Shc under these conditions. In turn, Shc bound Grb-2 and Sos which resulted in the activation of MAP kinase. The pure antiestrogen, ICI 182,780, blocked several steps in the rapidly responding ER alpha, Shc, MAP kinase pathway. These non-genomic effects of estradiol produced biologic effects by activating Elk and by inducing morphologic changes in cell membranes. Using confocal microscopy, we demonstrated that estradiol caused a rapid alteration in membrane ruffling, the formation of pseudopodia and translocation of ER alpha to regions contiguous with the cell membrane. These morphologic effects could be blocked with a pure anti-estrogen. We conclude that long-term estradiol deprived cells utilize both genomic (transcriptional) and rapid, non-genomic estradiol induced pathways. We postulate that synergy between these two pathways acting at the level of the cell cycle is responsible for adaptive hypersensitivity.
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PMID:Adaptive mechanisms induced by long-term estrogen deprivation in breast cancer cells. 1216 Sep 99

In order to identify metastasis-associated and promoting genes of pancreatic carcinoma we investigated the transcriptional profile of rat pancreatic carcinoma cell lines BSp73-AS (non-metastatic) and BSp73-ASML (highly metastatic) with Affymetrix GeneChip Array technology. We analyzed the expression profile of 7000 genes. Two hundred and ten genes (3%) were up-regulated and 247 genes (3.5%) were down-regulated in the metastatic cell line based on a fold change of expression of at least 3 and a change factor quality of > or = 2. In order to classify the de-regulated genes we defined the following categories: proteases and protease-related genes, cytokines, receptor tyrosine kinases, other transmembrane proteins/receptors, transcription, cell cycle/apoptosis, signaling, adhesion/extracellular matrix, metabolism, detoxification, protein modification, trafficking, immune response and other genes. We identified de-regulated AP1, FRA-1 and c-myc-mediated transcription in cell line BSp73-ASML. Up-regulation of transmembrane tyrosine kinase receptors c-met, IGFR1, IGFR2 and EGFR family-related ligands such as HB-EGF, TGFa, amphiregulin and neuregulin as well as c-met ligand HGF point to a possible role of this system in metastasis. We identified 56 non-tyrosine kinase transmembrane receptors as new target candidates for inhibition of metastasis, four of them representing already validated targets. In addition, we identified MMP9, uPA, uPAR, cyclin D1 and S100A4 (mts1) as possible contributors of the metastatic phenotype.
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PMID:Identification of rat pancreatic carcinoma genes associated with lymphogenous metastasis. 1217 79

The majority of pediatric anaplastic large cell lymphomas (ALCLs) carry the t(2;5)(p23;q35) chromosomal translocation that juxtaposes the dimerization domain of nucleophosmin with anaplastic lymphoma kinase (ALK). The nucleophosmin-ALK fusion induces constitutive, ligand-independent activation of the ALK tyrosine kinase leading to aberrant activation of cellular signaling pathways. To study the early consequences of ectopic ALK activation, a GyrB-ALK fusion was constructed that allowed regulated dimerization with the addition of coumermycin. Expression of the fusion protein caused a coumermycin-dependent increase in cellular tyrosine phosphorylation and c-Myc immunoreactivity, which was paralleled by a rise in c-myc RNA. To assess the clinical relevance of this observation, c-Myc expression was determined in pediatric ALK-positive and -negative lymphomas. Co-expression of c-Myc and ALK was seen in tumor cells in 15 of 15 (100%) ALK-positive ALCL samples, whereas no expression of either ALK or c-Myc was seen in six of six cases of ALK-negative T-cell lymphoma. C-Myc may be a downstream target of ALK signaling and its expression a defining characteristic of ALK-positive ALCLs.
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PMID:The nucleophosmin-anaplastic lymphoma kinase fusion protein induces c-Myc expression in pediatric anaplastic large cell lymphomas. 1221 16

The development of cervical carcinoma is closely associated with HPV infection. However, other genetic alterations also play an important role. In this study, we analyzed copy number alterations of several oncogene loci in a panel of 84 cervical tumors. Sixty-five (77%) tumors were HPV DNA-positive, and most were infected with type 16 or type 18 or both. The oncogenes studied include PIK3CA at 3q26.3, TERT at 5p15.33, C-MYC at 8q24, CCND1 at 11q13.3, ERBB2 at 17q21.2 and locus region 20q13.2. Amplification of 1 or more genes was detected in 55 (65%) cases using interphase FISH. PIK3CA was amplified in 43% of tumors, followed by TERT (33%), 20q13.2 (30%), ERBB2 (29%), C-MYC (25%) and CCND1 (12%). Most tumors showed low-level amplification with 3-7 copies of these genes, and complex changes involving 3 or more genes occur more frequently in tumors at advanced stages. Increased protein expression of c-erbB2 and c-myc was observed in tumors with the corresponding gene amplification. Oncogene alterations were found more often in HPV-infected cases, particularly for C-MYC and TERT. These findings indicate that HPV-associated cervical carcinomas bear frequent alterations of these genes, which may have critical biologic impact on the development and progression of carcinoma of the uterine cervix.
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PMID:Genetic alterations in cervical carcinomas: frequent low-level amplifications of oncogenes are associated with human papillomavirus infection. 1221 70

Bombesin (BN) and its mammalian homologue gastrin-releasing peptide (GRP) have been shown to play an important role in human cancer as autocrine and paracrine growth factors. Prostatic neuroendocrine cells are thought to secrete these regulatory peptides and they may therefore interact with their specific, aberrantly expressed GRP receptor (GRP-R) in prostate cancer. In this study, we investigated the effect of BN on immediate early gene expression in two androgen-independent prostate cancer cell lines DU-145 and PC-3 with functional GRP receptor. We found that BN induced c-fos mRNA expression in both cell lines in a time-dependent manner. In contrast, c-jun mRNA was only modestly induced in DU-145 cells but not at all in PC-3 cells. On the protein level, we detected BN-induced stimulation of the c-fos gene product but not of c-jun protein. Sustained increase of the c-myc gene product was detectable in PC-3 but not in DU-145 cells. Concurrently, we demonstrated BN-dependent activation of the transcription factor Elk-1 and significant increase of cell proliferation in both prostate cancer cell lines. Taken together, these data suggest that BN acts as a mitogen in prostate cancer and this might be associated with the activation of the transcription factor Elk-1 and the immediate early gene c-fos.
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PMID:GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells. 1240 26


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