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)

Signal transduction downstream HGF receptor (MET) activation involves multiple pathways that account for mitogenesis, motility and morphogenesis in a cell type-dependent fashion. MET receptor is aberrantly expressed in almost 100% of human osteosarcomas. We analyzed the effect of the MET receptor activation in five human osteosarcoma cell lines evaluating the levels of HGF-dependent activation of MAPK and PKB/AKT as biochemical readouts of mitogenic and invasive responses, respectively. All the cell lines tested expressed high levels of the MET proto-oncogene. Four cell lines showed activation of the MAPK cascade upon HGF stimulation, suggesting that this growth factor serves a common proliferative function in osteosarcomas. Two lines showed activation of PKB/AKT that is known to be involved in migration mediated by HGF receptor. Accordingly, cell lines where MAPK cascade was activated responded to HGF with increased proliferation, while induction and inhibition of PKB/AKT activity corresponded to acquisition or block of the invasive-motile response to HGF, respectively. Both the HGF dependent responses were reverted by the specific MET inhibitor K252a. These data show that HGF activates both the mitogen and motogen machinery in osteosarcoma cells and suggest that HGF might promote their malignant behavior by concomitant activation of different pathways and biological functions.
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PMID:Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma. 1270 13

Tumor response to preoperative chemotherapy is an important prognostic factor for localized, operable extremity osteosarcoma. Other clinical variables include tumor size and location, age and sex, and serum enzymes. Advances in molecular oncology yielded a second group of factors such as multidrug resistance status, loss of heterozygosity of RB gene, and HER2/erbB-2 expression. The aim of this study was to investigate the expression and the prognostic value of the newly described erbB-4 receptor in specimens from adults with bone sarcomas treated by pre- and postoperative chemotherapy. Thirty-three patients with non-metastatic bone sarcoma have been treated by two doxorubicin-based induction chemotherapy regimen, followed by limb sparing surgery and tailored adjuvant chemotherapy. Pre-chemotherapy tissue specimens were investigated for the expression of erbB-4 receptor and post-induction specimens were assessed for pathological response. The clinical response rates were 32-36%. The degree of induced necrosis was correlated with the disease-free survival (DFS). Patients achieving >/=90% necrosis had an improved DFS over patients with poor histological response. ErbB-4 expression was significantly associated with poor histologic response and shorter DFS. ErbB-4 expression may be used for prognostication of adults with bone sarcomas.
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PMID:Induction chemotherapy for bone sarcoma in adults: correlation of results with erbB-4 expression. 1288 46

An increase in the interaction between advanced glycation end-products (AGEs) and their receptor RAGE is believed to contribute to the pathogenesis of chronic complications of Diabetes mellitus, which can include bone alterations such as osteopenia. We have recently found that extracellular AGEs can directly regulate the growth and development of rat osteosarcoma UMR106 cells, and of mouse calvaria-derived MC3T3E1 osteoblasts throughout their successive developmental stages (proliferation, differentiation and mineralisation), possibly by the recognition of AGEs moieties by specific osteoblastic receptors which are present in both cell lines. In the present study we examined the possible expression of RAGE by UMR106 and MC3T3E1 osteoblastic cells, by immunoblot analysis. We also investigated whether short-, medium- or long-term exposure of osteoblasts to extracellular AGEs, could modify their affinity constant and maximal binding for AGEs (by 125I-AGE-BSA binding experiments), their expression of RAGE (by immunoblot analysis) and the activation status of the osteoblastic ERK 1/2 signal transduction mechanism (by immunoblot analysis for ERK and P-ERK). Our results show that both osteoblastic cell lines express readily detectable levels of RAGE. Short-term exposure of phenotypically mature osteoblastic UMR106 cells to AGEs decrease the cellular density of AGE-binding sites while increasing the affinity of these sites for AGEs. This culture condition also dose-dependently increased the expression of RAGE and the activation of ERK. In proliferating MC3T3E1 pre-osteoblasts, 24-72 h exposure to AGEs did not modify expression of RAGE, ERK activation or the cellular density of AGE-binding sites. However, it did change the affinity of these binding sites forAGEs, with both higher- and lower-affinity sites now being apparent. Medium-term ( 1 week) incubation of differentiated MC3T3E1 osteoblasts with AGEs, induced a simultaneous increase in RAGE expression and in the relative amount of P-ERK. Mineralising MC3T3E1 cultures grown for 3 weeks in the presence of extracellular AGEs showed a decrease both in RAGE and P-ERK expression. These results indicate that, in phenotypically mature osteoblastic cells, changes in ERK activation closely follow the AGEs-induced regulation of RAGE expression. Thus, the AGEs-induced biological effects that we have observed previously in osteoblasts, could be mediated by RAGE in the later stages of development, and mediated by other AGE receptors in the earlier pre-osteoblastic stage.
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PMID:Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). 1296 37

Lung metastasis has a great influence on the prognosis of patients with osteosarcoma. We previously established two high-metastatic sublines, M112 and M132, from the HuO9 human osteosarcoma cell line by in vivo selection. In this study, we newly isolated a high-metastatic subline, H3, and three low-metastatic sublines, L6, L12 and L13, from HuO9 by the dilution plating method. Three high-metastatic sublines produced more than 200 metastatic nodules in the lung, while three low-metastatic sublines produced no or few nodules after injection of 2 x 10(6) cells into the tail vein of nude mice. There were significant differences in the motility and invasiveness between high- and low-metastatic sublines, whereas the growth rates in vitro and the tumorigenicity in vivo showed no correlation with their metastatic abilities. Early adherence to culture plates was significantly lower in two of three low-metastatic sublines, which occupied smaller surface areas on the culture plates than other sublines did. Comparison of the expression of 637 cancer-related genes by cDNA microarray revealed that seven genes were differentially expressed between high- and low-metastatic sublines. Among them, five genes (AXL, TGFA, COLL7A1, WNT5A, and MKK6) were associated with adherence, motility, and/or invasiveness. These results suggest that the differences in motility/invasiveness and adhesive abilities are key determinants of lung metastasis in osteosarcoma.
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PMID:Biological properties and gene expression associated with metastatic potential of human osteosarcoma. 1466 98

Recent animal studies suggested that deregulated expression of the platelet-derived growth factor receptor alpha (PDGFRalpha) may contribute to the failure of normal neural tube closure (NTC). There is also suggestive evidence that the promoter haplotype of the PDGFRA is associated with genetic susceptibility in human neural tube defects (NTDs). The purpose of our study was to investigate the association between promoter haplotype combinations of the human PDGFRA gene and risk for NTDs in a Hispanic population from the Texas-Mexico border region. This population has a considerably higher prevalence of NTDs (16/10,000 live births) than that generally reported in the United States (8-10/10,000 live births). In the present study, NTDs were defined as spina bifida or anencephaly. The haplotype of PDGFRA gene promoter was determined by direct DNA sequence analysis. Two novel haplotypes, H2epsilon and H1beta, were found. We observed significant differences among variable haplotype groups from in vitro transient transfection studies in U2-OS osteosarcoma cell and two other cell lines (HeLa cell and MCF7 cell). Result from our case-control study demonstrated that the frequencies of haplotypes with low transcription activity were significantly higher in NTD mothers than that observed in control mothers (odds ratio=2.2, 95% CI=1.0-4.6). Infants with at least one low activity allele showed slightly higher risk (odds ratio=1.5, 95%=0.8-3.1). Our study suggests that the reduced transcriptional activity of PDGFRA gene could increase the risk of having an NTD-affected pregnancy.
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PMID:Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects. 1474 Nov 94

The overexpression of HER-2/neu and p53 has been associated with poor outcome in many neoplasms. Their role in patients with osteosarcoma is unclear. We studied the expression of HER-2/neu and p53 in 22 osteosarcoma samples (from 20 patients--2 had locally recurrent disease) biopsied at the University of Medicine and Dentistry of New Jersey (UMDNJ) from 1996-2000 using both immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis. Fourteen patients (14 samples) presented with Stage II and 6 patients (8 samples) presented with Stage III disease. Median follow-up is two years (range one year to five years). Four of 22 (18%) samples showed focal membranous or cytoplasmic positivity for HER-2/neu and six of 22 samples (27%) showed nuclear positivity for p53 by IHC analysis. In contrast, none of 22 tested samples showed gene amplification for HER-2/neu by FISH analysis. Seven of 13 HER-2/neu and p53 negative patients (54%) are currently disease free (between one year to five years). In this sample of patients, the HER-2/neu oncogene is not overexpressed or amplified in osteosarcoma; six of 22 samples (27%) showed overexpression of p53 by IHC analysis. By FISH, none of the samples demonstrated deletion of p53. Neither HER2/neu nor p53 expression was important for the biology of osteosarcoma in this population.
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PMID:HER-2/neu and p53 in osteosarcoma: an immunohistochemical and fluorescence in situ hybridization analysis. 1506 60

Clear cell sarcoma of soft tissue (CCSST), also known as malignant melanoma of soft parts, represents a rare lesion of the musculoskeletal system usually affecting adolescents and young adults. CCSST is typified by a chromosomal t(12;22)(q13;q12) translocation resulting in a fusion between the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1), of which the activity in nontransformed cells is regulated by cyclic AMP. Our aim was to identify critical differentially expressed genes in CCSST tumor cells in comparison with other solid tumors affecting children and young adults to better understand signaling pathways regulating specific features of the development and progression of this tumor entity. We applied Affymetrix Human Genome U95Av2 oligonucleotide microarrays representing approximately 12,000 genes to generate the expression profiles of the CCSST cell lines GG-62, DTC-1, KAO, MST2, MST3, and Su-CC-S1 in comparison with 8 neuroblastoma, 7 Ewing tumor, and 6 osteosarcoma cell lines. Subsequent hierarchical clustering of microarray data clearly separated all four of the tumor types from each other and identified differentially expressed transcripts, which are characteristically up-regulated in CCSST. Statistical analysis revealed a group of 331 probe sets, representing approximately 300 significant (P < 0.001) differentially regulated genes, which clearly discriminated between the CCSST and other tumor samples. Besides genes that were already known to be highly expressed in CCSST, like S100A11 (S100 protein) or MITF (microphthalmia-associated transcription factor), this group shows an obvious portion of genes that are involved in cyclic AMP response or regulation, in pigmentation processes, or in neuronal structure and signaling. Comparison with other expression profile analyses on neuroectodermal childhood tumors confirms the high robustness of this strategy to characterize tumor entities based on their gene expression. We found the avian erythroblastic leukemia viral oncogene homologue 3 (ERBB3) to be one of the most dramatically up-regulated genes in CCSST. Quantitative real-time PCR and Northern blot analysis verified the mRNA abundance and confirmed the absence of the inhibitory transcript variant of this gene. The protein product of the member of the epidermal growth factor receptor family ERBB3 could be shown to be highly present in all of the CCSST cell lines investigated, as well as in 18 of 20 primary tumor biopsies. In conclusion, our data demonstrate new aspects of the phenotype and the biological behavior of CCSST and reveal ERBB3 to be a useful diagnostic marker.
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PMID:Expression profiling of t(12;22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3. 1515 91

Low-grade osteosarcoma is a rare variant of osteosarcoma. Although malignant, it must be distinguished from conventional osteosarcomas because of its excellent prognosis. Numerous published papers have described the expression of HER2/neu oncogene in osteosarcoma as a poor prognostic factor; however their results are discordant. To address the expression of HER2/neu and to validate the assessment methods of amplification of the HER2/neu oncogene, the authors have employed quantitative real-time PCR and fluorencent in situ hybridization analysis (FISH) in 21 low-grade osteosarcomas. We calculated the quantification of HER2/neu oncogene amplification as the ratio of measured HER2/neu gene/beta-globin reference gene in real-time PCR. All 21 cases had amplified signals in the quantitative real-time PCR. However, in the FISH analysis, HER2/neu oncogene amplification was only identified in 26% (5/19). The exact reasons for the discordance between these two methods are unknown; however, variable histological features might play a potential role. In conclusion, as our study showed amplification of HER2/neu oncogene in low-grade osteosarcoma, we assume that expression of HER2/neu is not a poor prognostic factor in low-grade osteosarcoma.
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PMID:Quantitative assessment of HER2/neu expression by real-time PCR and fluorescent in situ hybridization analysis in low-grade osteosarcoma. 1520 72

The INK4A/ARF locus on chromosome 9 is a tumor suppressor gene frequently mutated in human cancers. In order to study the effects of p14ARF expression in tumor cells, we constructed a recombinant adenovirus containing p14ARF cDNA (Adp14ARF). Adp14ARF infection of U2OS osteosarcoma cells which has wild type p53 and mutant p14ARF revealed high levels of p14 (ARF) expression within 24h. In addition, Adp14ARF-mediated expressing of p14 (ARF) was associated with increased levels of p53, p21, and mdm2 protein. Growth inhibition assays following Adp14ARF infection demonstrated that the growth of U2OS cells was inhibited relative to infection with control virus. Furthermore, TUNEL analysis as well as PARP cleavage assays demonstrated that Adp14ARF infection was associated with increased apoptosis in U2OS cell line and that it was associated with Adp14ARF induced overexpression of Fas and Fas-L. Addition of Fas-L neutralizing antibody NOK-1 decreased Adp14-mediated cell death, indicating that p14 (ARF) induction of the Fas pathway is associated with increased apoptosis. The finding that Adp14ARF infection did not induce Fas expression in U2OS/E6 and MCF/E6 cells suggests that wild type p53 expression may be necessary for Adp14ARF-mediated induction of Fas. The observation that overexpression of p53 by Adp53 infection in MCF-7 does not induce increased Fas protein levels nor apoptotic cell death suggests that p53 overexpression is required but not sufficient enough for apoptosis. These studies suggest there are other mechanisms other than induction of p53 in ARF-mediated apoptosis and gene therapy using Adp14ARF may be a promising treatment option for human cancers containing wild type p53 and mutant or deleted p14 expression.
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PMID:Apoptosis induced by adenovirus-mediated p14ARF expression in U2OS osteosarcoma cells is associated with increased Fas expression. 1520 13

In a series of experimental studies, it was shown that repetitive mild heat stress has antiaging hormetic effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. We have reported the hormetic effects of repeated challenge at the levels of maintenance of stress protein profile; reduction in the accumulation of oxidatively and glycoxidatively damaged proteins; stimulation of the proteasomal activities for the degradation of abnormal proteins; improved cellular resistance to ethanol, hydrogen peroxide, and ultraviolet-B rays; and enhanced levels of various antioxidant enzymes. Detailed analysis of the signal transduction pathways to determine alterations in the phosphorylation and dephosphorylation states of ERK, JNK, and p38 MAP kinases as a measure of cellular responsiveness to mild and severe heat stress is in progress. Furthermore, comparative studies using nonaging immortal cell lines, such as SV40-transformed human fibroblasts, spontaneous osteosarcoma cells, and telomerase-immortalized human bone marrow cells are also in progress for establishing differences in normal and cancerous cells for their responsiveness to mild and severe stresses.
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PMID:Mechanisms of hormesis through mild heat stress on human cells. 1524 85


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