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)

Neuroectodermal tumor cells, like neural crest (NC) cells, are pluripotent, proliferative, and migratory. We tested the hypothesis that genetic programs essential to NC development are activated in neuroectodermal tumors. We examined the expression of transcription factors PAX3, PAX7, AP-2alpha, and SOX10 in human embryos and neuroectodermal tumors: neurofibroma, schwannoma, neuroblastoma, malignant nerve sheath tumor, melanoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, and Ewing's sarcoma. We also examined the expression of P0, ERBB3, and STX, targets of SOX10, AP-2alpha, and PAX3, respectively. PAX3, AP-2alpha, and SOX10 were expressed sequentially in human NC development, whereas PAX7 was restricted to mesoderm. Tumors expressed PAX3, AP-2alpha, SOX10, and PAX7 in specific combinations. SOX10 and AP-2alpha were expressed in relatively differentiated neoplasms. The early NC marker, PAX3, and its homologue, PAX7, were detected in poorly differentiated tumors and tumors with malignant potential. Expression of NC transcription factors and target genes correlated. Transcription factors essential to NC development are thus present in neuroectodermal tumors. Correlation of specific NC transcription factors with phenotype, and with expression of specific downstream genes, provides evidence that these transcription factors actively influence gene expression and tumor behavior. These findings suggest that PAX3, PAX7, AP-2alpha, and SOX10 are potential markers of prognosis and targets for therapeutic intervention.
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PMID:Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. 1603 8

Vascular endothelial growth factor (VEGF) is a potent signalling molecule that acts through two tyrosine kinase receptors, VEGFR1 and VEGFR2. The upregulation of VEGF and its receptors is important in tumour-associated angiogenesis; however, recent studies suggest that several tumour cells express VEGF receptors and may be influenced by autocrine VEGF signalling. Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, and is dependent on autocrine signalling for its growth. The alveolar subtype of RMS is often characterized by the presence of a PAX3-FKHR translocation, and when introduced into non-RMS cells, the resultant fusion protein induces expression of VEGFR1. In our study, we examined the expression of VEGF and its receptors in RMS, and autocrine effects of VEGF on cell growth. VEGF and receptor mRNA and protein were found to be expressed in RMS cells. Exogenous VEGF addition resulted in extracellular signal-regulated kinase-1/2 phosphorylation and cell proliferation, and both were reduced by VEGFR1 blockade. Growth was also slowed by VEGFR1 inhibitor alone. Treatment of RMS cells with all-trans-retinoic acid decreased VEGF secretion and slowed cell growth, which was rescued by VEGF. These data suggest that autocrine VEGF signalling likely influences RMS growth and its inhibition may be an effective treatment for RMS.
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PMID:Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid. 1611 81

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. The simultaneous loss of Ink4a/Arf function and disruption of Met signaling in Ink4a/Arf-/- mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. To address the roles of MET and CDKN2A (p16INK4A/p14ARF) in human RMS, we performed mutational analyses in 39 samples of RMS by PCR-SSCP. No mutations were detected in exons 14-21 of MET whereas a nonsense mutation at codon 80 of p16(INK4A) was identified in an alveolar RMS cell line. We also quantified the relative expression levels and DNA copy numbers of these genes in seven cell lines and 17 fresh tumors by real-time quantitative PCR. Expression of MET was detected in all samples; however, more than 10-fold difference was found in the samples with higher or lower expression level, despite a normal DNA copy number. The protein expression level was consistent with that of mRNA, and in cell lines with a higher expression level, MET was constitutively activated. Notably, the expression level of MET was significantly higher in patients who died (P = 0.02), in patients with stage IV (P = 0.04), as well as in patients with PAX3-FKHR chimeric transcript (P = 0.04). On the other hand, reduced or absent expression of p16INK4A and/or p14(ARF) showed no significant correlation with the clinicopathological parameters, except for the age at diagnosis. Our data suggest that MET plays a role in the progression of RMS.
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PMID:Mutation and expression analyses of the MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression. 1724 66

The malignancy of alveolar rhabdomyosarcoma (ARMS) has been linked to expression of the PAX3-FKHR chimeric gene. To understand the effect of this gene, we used RNAi to knock down its expression (without affecting the expressions of either PAX3 or FKHR) in human ARMS cell lines. Down-regulating PAX3-FKHR caused (a) tumor cells to accumulate in the G1 phase, inhibiting the rate of cellular proliferation, (b) a reduction in the levels of the MET, reducing cell motility stimulated by HGF, and (c) induction of the myogenic differentiation gene, myogenin, and muscle differentiation (morphologic change and the expression of muscle specific proteins, desmin, and myosin heavy chain). These results suggest that PAX3-FKHR in ARMS cells promotes malignant phenotypes such as proliferation, motility, and to suppress differentiation.
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PMID:Effects of PAX3-FKHR on malignant phenotypes in alveolar rhabdomyosarcoma. 1802 85

Immunohistochemical staining for anaplastic lymphoma kinase (ALK) has been described in rhabdomyosarcomas (RMS), especially the alveolar subtype. Previous studies have yielded conflicting results regarding the pattern of staining (nuclear versus cytoplasmic), and there has been no correlation with PAX3-7/FKHR fusion status. This study was undertaken to evaluate ALK receptor protein expression in a large series of RMS; to correlate these results with fusion status; and to investigate the possibility of 2p23 amplification or translocation using fluorescence in situ hybridization (FISH). Sixty-nine cases of RMS were examined and classified as alveolar RMS (ARMS), embryonal RMS (ERMS), or unclassifiable RMS (URMS) subtypes. Anaplastic lymphoma kinase immunohistochemistry was performed using anti-human CD246 antibody; cases were considered positive when more than 50% of cells had moderate or intense cytoplasmic and/or nuclear staining. There were 30 ARMS, 37 ERMS, and 2 URMS subtypes. Reverse transcription-polymerase chain reaction for PAX3/PAX7-FKHR fusion analysis had been done in all cases of ARMS, in 27 of 37 cases of ERMS, and in both URMS cases. Anaplastic lymphoma kinase staining was positive in 16 of 30 ARMS (53%) and 9 of 39 nonalveolar RMS (23%) cases (P < 0.05). Of the 21 ARMS cases with PAX3-FKHR fusion, 10 of 21 (48%) were positive for ALK staining; of the 6 ARMS cases with PAX7-FKHR fusion, 3 of 6 (50%) were positive for ALK staining; and 3 of 3 (100%) of the fusion-negative ARMS were positive with ALK staining. When comparing each of the ARMS subtypes, statistical significance was not reached. All positive cases showed dot-like cytoplasmic staining; nuclear staining was not seen. Of a subset of 6 ALK-positive ARMS submitted for break-apart FISH for the ALK locus, there was no evidence of a translocation; 1 case had ALK amplification and 2 had low-level gains of the ALK gene. We conclude that there is ALK overexpression in RMS, more commonly in ARMS than in ERMS, most likely independent of fusion status. Amplification or upregulation of ALK may underlie ALK protein overexpression.
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PMID:ALK expression in rhabdomyosarcomas: correlation with histologic subtype and fusion status. 1878 87

Recent studies have shown a significant involvement of insulin-like growth factor (IGF) signaling components in the pathogenesis of rhabdomyosarcoma (RMS). Furthermore, there has been some evidence to indicate that differential expression of IGF pathway genes can distinguish RMS subtypes. The present study utilized immunohistochemistry to determine the expression patterns of IGF1, IGF2, IGF binding protein 2 (IGFBP2), IGF receptor 1 (IGF1R), and IGF receptor 2 (IGF2R) in 24 embryonal RMS (ERMS) and 8 alveolar RMS (ARMS). A majority of tumors were positive for IGF2, IGFBP2, IGF1R, and IGF2R and negative for IGF1 expression. However, only IGF2 showed a significant difference in expression between the ERMS and ARMS subtypes, with higher levels of expression in ERMS (P = 0.0003). Within the ARMS subtype, IGF2 positivity was limited to PAX/FKHR translocation-negative tumors. The staining pattern for all 5 proteins was diffuse cytoplasmic in the majority of tumors. Analysis of RMS cell lines by real-time reverse transcriptase-polymerase chain reaction for IGF2 expression revealed significantly higher mean expression levels in ERMS and translocation-negative ARMS cell lines when compared to translocation-positive ARMS cell lines (P = 0.0027). Stable introduction of PAX3/FKHR into an ERMS cell line also demonstrated a significant reduction in IGF2 expression. The results of this study show that expression of the IGF2 ligand is associated with translocation-negative tumors and may serve as a diagnostic aid in distinguishing RMS subtypes. Furthermore, the in vitro results are supportive of a role for the PAX3/FKHR fusion gene in the inhibition of IGF2 expression.
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PMID:Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors. 1878 88

Human neurocristopathies include a number of syndromes, tumors, and dysmorphologies of neural crest (NC) stem cell derivatives. In recent years, many white spotting genes have been associated with hypopigmentary disorders and deafness in neurocristopathies resulting from NC stem cell-derived melanocyte deficiency during development. These include PAX3, SOX10, MITF, SNAI2, EDNRB, EDN3, KIT, and KITL. Recent studies have revealed surprising new insights into a central role of MITF in the complex network of interacting genes in melanocyte development. In this perspective, we provide an overview of some of the current findings and explore complex functional roles of these genes during NC stem cell-derived melanocyte development.
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PMID:Transcriptional and signaling regulation in neural crest stem cell-derived melanocyte development: do all roads lead to Mitf? 1900 57

Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. They resemble developing skeletal muscle and are histologically divided into two main subtypes; alveolar and embryonal RMS. Characteristic genomic aberrations, including the PAX3- and PAX7-FOXO1 fusion genes in alveolar cases, have led to increased understanding of their molecular biology. Here, we determined the effect of genomic copy number on gene expression levels through array comparative genomic hybridization (CGH) analysis of 13 RMS cell lines, confirmed by multiplex ligation-dependent probe amplification copy number analyses, combined with their corresponding expression profiles. Genes altered at the transcriptional level by genomic imbalances were identified and the effect on expression was proportional to the level of genomic imbalance. Extrapolating to a public expression profiling dataset for 132 primary RMS identified features common to the cell lines and primary samples and associations with subtypes and fusion gene status. Genes identified such as CDK4 and MYCN are known to be amplified, overexpressed, and involved in RMS tumorigenesis. Of the many genes identified, those with likely functional relevance included CENPF, DTL, MYC, EYA2, and FGFR1. Copy number and expression of FGFR1 was validated in additional primary material and found amplified in 6 out of 196 cases and overexpressed relative to skeletal muscle and myoblasts, with significantly higher expression levels in the embryonal compared with alveolar subtypes. This illustrates the ability to identify genes of potential significance in tumor development through combining genomic and transcriptomic profiles from representative cell lines with publicly available expression profiling data from primary tumors.
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PMID:Genomic imbalances in rhabdomyosarcoma cell lines affect expression of genes frequently altered in primary tumors: an approach to identify candidate genes involved in tumor development. 1923 22

Human pigmentation appears to be one of the main modulators of individual risk of developing malignant melanoma (MM). A large number of genes are known to be involved in rare pigmentary disorders and explain most of the variation in pigmentation phenotypes seen in human populations. This Spanish case-control study included 205 patients with melanoma and 245 control subjects. Thirty-one single nucleotide polymorphisms (SNPs) in genes that had been mainly associated with congenital pigmentation syndromes (ADTB3A, ATRN, CHS1, EDNRB, HPS, KIT, MGRN1, MITF, MLANA, MYO5A, MYO7A, OA1, OCA2, PAX3 and SOX10) were selected. We found that the variant allele of OCA2 R419Q (rs1800407) was associated with increased risk of MM (OR 1.55, 95% CI 1.04-2.31, P = 0.03). This effect on melanoma risk appeared to be stronger among individuals with solar lentigines, or at least 50 nevi. We also describe, for the first time, an association with the variant S1666C (rs2276288) in the MYO7A gene (OR 1.35; 95% CI 1.04-1.76; P = 0.03). Again, this association appeared to be stronger in several phenotypic groups such as individuals with fair skin and those with childhood sunburns. We also found that several variants in the pigmentation genes considered were associated with intermediate phenotypic characteristics. Our findings highlight the potential importance of pigmentation genes in sporadic MM susceptibility.
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PMID:Pigmentation-related genes and their implication in malignant melanoma susceptibility. 1932 Jul 33

Melanoma is a cancer with a poorly understood molecular pathobiology. We find the transcription factors PAX3, SOX10, MITF, and the tyrosine kinase receptor MET expressed in melanoma cell lines and primary tumors. Analysis for MET expression in primary tumor specimens showed 27/40 (68%) of the samples displayed an increased expression of MET, and this expression was highly correlated with parallel expression of PAX3, SOX10, and MITF. PAX3 and MITF bind to elements in the MET promoter independently, without evidence of either synergistic activation or inhibition. SOX10 does not directly activate the MET gene alone, but can synergistically activate MET expression with either PAX3 or MITF. In melanoma cells, there was evidence of two pathways for PAX3 mediated MET induction: (i) direct activation of the gene, and (ii) indirect regulation through MITF. SK-MEL23 melanoma cells have both of these pathways intact, while SK-MEL28 melanoma cells only have the first pathway. In summary, we find that PAX3, SOX10 and MITF play an active role in melanoma cells by regulating the MET gene. In consequence, MET promotes the melanoma cancer phenotype by promoting migration, invasion, resistance to apoptosis, and tumor cell growth.
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PMID:PAX3 and SOX10 activate MET receptor expression in melanoma. 2006 53


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