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)

Neurotrophins and their cognate receptors play a pivotal role in the development and function of the nervous system. High expression levels of the neurotrophin receptor TrkB and its ligands in neuroblastomas are associated with an unfavorable outcome. We report here that NTRK2, which encodes the TrkB receptor tyrosine kinase, is an oxygen-regulated gene, whose expression is stimulated by the hypoxia-inducible factor-1 (HIF-1). TrkB mRNA and protein levels were elevated nearly 30-fold in neuroblastoma-derived Kelly cells in hypoxia (1% O(2)) versus normoxia (21% O(2)). A luciferase reporter construct containing approximately 2.1 kilobases of the human TrkB promoter was activated about 6-fold both in hypoxia and after stimulation with the hypoxia mimetic 2,2'-dipyridyl (100 microm) at 21% O(2). Luciferase activity in the presence of 2,2'-dipyridyl was reduced significantly upon small interfering RNA knockdown of HIF-1alpha but not of HIF-2alpha. Accordingly, hypoxia failed to stimulate the TrkB promoter in mouse embryonic fibroblasts that lacked HIF-1alpha. The hypoxia-responsive promoter region could be mapped to three HIF-1 binding elements that were located between -923 and -879 bp relative to the transcription start site. The migration of cultured neuroblastoma cells was increased approximately 2-fold upon incubation at 1 versus 21% O(2). This effect of hypoxia was abrogated with the tyrosine kinase inhibitor K252a (200 nm). Our findings indicate that transcription of the NTRK2 gene is stimulated at low oxygen tension through a HIF-1-dependent mechanism. In conclusion, enhanced expression of TrkB could represent a critical switch for the previously reported dedifferentiation of neuroblastoma cells under hypoxic conditions.
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PMID:Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of the TrkB neurotrophin receptor gene. 1737 10

The determination of gene-by-gene and gene-by-environment interactions has long been one of the greatest challenges in genetics. The traditional methods are typically inadequate because of the problem referred to as the "curse of dimensionality." Recent combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method, the combinatorial partitioning method, and the restricted partition method, have a straightforward correspondence to the concept of the phenotypic landscape that unifies biological, statistical genetics, and evolutionary theories. However, the existing approaches have several limitations, such as not allowing for covariates, that restrict their practical use. In this study, we report a generalized MDR (GMDR) method that permits adjustment for discrete and quantitative covariates and is applicable to both dichotomous and continuous phenotypes in various population-based study designs. Computer simulations indicated that the GMDR method has superior performance in its ability to identify epistatic loci, compared with current methods in the literature. We applied our proposed method to a genetics study of four genes that were reported to be associated with nicotine dependence and found significant joint action between CHRNB4 and NTRK2. Moreover, our example illustrates that the newly proposed GMDR approach can increase prediction ability, suggesting that its use is justified in practice. In summary, GMDR serves the purpose of identifying contributors to population variation better than do the other existing methods.
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PMID:A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. 1750 30

Runx3, a Runt domain transcription factor, determines neurotrophin receptor phenotype in dorsal root ganglion (DRG) neurons. Molecular mechanisms by which Runx3 controls distinct neurotrophin receptors are largely unknown. Here, we show that RUNX3 abolished mRNA induction of TRKB expression, and concomitantly altered the neurotrophin response in a differentiating neuroblastoma cell line. In contrast, RUNX3 did not play a significant role in TRKC regulation even under the relevant BMP signaling pathway. We identified putative regulatory elements of Ntrk2/NTRK2 (a gene that codes for TrkB) using an unbiased computational approach. One of these elements was a highly conserved intronic sequence that contains a cluster of Runx binding sites. In a primary culture of DRG neurons, endogenous Runx3 bound to the consensus cluster, which had repressor activity against the Ntrk2 promoter under the control of NT-3 signaling. Consistent with these findings, Runx3-deficient embryos showed an increased number of trkB+ DRG neurons and failed to maintain trkC expression. Taken together, Runx3 determines TrkC positive sensory neuron identities through the transcriptional repression of TrkB when Trk-BTrkC double positive neurons differentiate into TrkC single positive neurons.
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PMID:The transcription factor Runx3 represses the neurotrophin receptor TrkB during lineage commitment of dorsal root ganglion neurons. 1758 46

Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TRK) signaling pathway activates a wide range of downstream intracellular cascades, regulating neuronal development and plasticity, long-term potentiation, and apoptosis. The NTRK family encodes the receptors TRKA, TRKB, and TRKC, to which the neurotrophins, nerve growth factor (NGF), BDNF and neurotrophin-3 (NT-3) bind, respectively, with high affinity. Signaling through these receptors appears to be compromised in Alzheimer's disease (AD). This study is the most comprehensive investigation of genetic variants of NTRK2, and the first to show significant association between NTRK2 with AD. Fourteen single nucleotide polymorphisms (SNPs), located in 8 of 18 linkage disequilibrium (LD) blocks, were genotyped in 203 families with at least two AD affected siblings with mean age of onset (MAO) of 70.9 +/- 7.4 years and one unaffected sibling from the NIMH-ADGJ dataset. Family based association testing found no single SNP association, however, significant associations were found for two and three locus haplotypes (P = 0.012, P = 0.009, respectively) containing SNPs rsl624327, rsl443445, and rs378645. These SNPs are located in areas of the gene containing sequences that could be involved in alternative splicing and/or regulation of NTRK2. Our results suggest that NTRK2 may be a genetic susceptibility gene contributing to AD pathology.
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PMID:Genetic association of neurotrophic tyrosine kinase receptor type 2 (NTRK2) With Alzheimer's disease. 1791 33

Disruptions in the expression of the BDNF gene that encodes a neurotrophic factor involved in neuronal survival, differentiation and synaptic plasticity has been proposed to contribute to the molecular pathogenesis of Rett syndrome. Rett syndrome (RTT) is a neurodevelopmental disorder, caused by mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2). MeCP2 deficiency in the brain has been shown to decrease overall expression of BDNF in spite of an observed increase in the activity of promoter III that appears to be controlled directly by MeCP2. Therefore, how MeCP2 deficiency causes an overall downregulation of BDNF expression was an enigma. Here we report that MeCP2 deficiency in human and mouse brain causes an increase in expression of two neuronal gene transcriptional repressors REST (RE1 silencing transcription factor), and CoREST. MeCP2 binds to and is involved in repression of Rest and CoRest promoters despite their unmethylated state. MeCP2 depletion is associated with a change in the histone modification profile to a more active conformation. The elevated levels of REST and CoREST in the brain of RTT patients and MeCP2 deficient mice result in downregulation of BDNF, apparently by their binding to the RE1 (element) located between the first two promoters of the BDNF gene. Interestingly, the NTRK2 gene that encodes the BDNF receptor, TRKB, was overexpressed in MeCP2 deficient human and mouse brains either directly or as an attempt to compensate for BDNF deficiency.
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PMID:MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. 1807 16

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 x 10(-4)) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 x 10(-5)) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.
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PMID:Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders. 1820 54

We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin-fixed, paraffin-embedded (FFPE) human esophageal carcinomas, mostly squamous-cell-carcinoma (ESCC), and their adjacent normal tissues. A total of 1,432 single nucleotide polymorphisms (SNPs) derived from 766 cancer-related genes were genotyped with partially degraded genomic DNAs isolated from these samples. This directly targeted genomic profiling identified not only previously reported somatic gene amplifications (e.g., CCND1) and deletions (e.g., CDKN2A and CDKN2B) but also novel genomic aberrations. Among these novel targets, the most frequently deleted genomic regions were chromosome 3p (including tumor suppressor genes FANCD2 and CTNNB1) and chromosome 5 (including tumor suppressor gene APC). The most frequently amplified genomic region was chromosome 3q (containing DVL3, MLF1, ABCC5, BCL6, AGTR1 and known oncogenes TNK2, TNFSF10, FGF12). The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases, suggesting a molecular mechanism for the generation of somatic chromosomal aberrations. We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes (CSF1, KIAA1804, IL2, PMS2, IRF7, FLT3, NTRK2, MAP3K9, ERBB2 and PRKAR1A), suggesting that they might play roles in esophageal cancer susceptibility and/or development. Taken together, our results demonstrated the utility of the BeadArray technology for high-throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer-related genes in human esophageal cancer.
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PMID:Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues. 1824 Oct 37

The neurotrophic tyrosine receptor kinase (NTRK) family is potentially implicated in tumorigenesis and progression of several neoplastic diseases, including lung cancer. We investigated a large number of pulmonary neuroendocrine tumors (PNETs) and non-small cell lung carcinomas (NSCLCs) without morphological evidence of neuroendocrine differentiation for mutations in the NTRK gene family. A total of 538 primary lung carcinomas, including 17 typical carcinoids (TCs), 10 atypical carcinoids (ACs), 39 small cell lung carcinomas (SCLCs), 29 large cell neuroendocrine carcinomas (LCNECs), and 443 NSCLCs were evaluated by single-strand conformation polymorphism (SSCP) and sequencing of the tyrosine kinase domain (TKD) of NTRK1, NTRK2, and NTRK3. The NTRK1 gene was never found to be mutated. A total of 10 somatic mutations were detected in NTRK2 and NTRK3, mostly located in the activating and catalytic loops. NTRK mutations were seen in 9 (10%) out of 95 PNETs but in 0 out of 443 NSCLCs investigated. No mutations were observed in TCs, ACs, and SCLCs. Interestingly, all the mutations were restricted to the LCNEC histotype, in which they accounted for 31% of cases. A mutational analysis, performed after microdissection of LCNECs combined with adenocarcinoma (ADC), showed that only neuroendocrine areas were positive, suggesting that NTRK mutations are involved in the genesis of the neuroendocrine component of combined LCNECs. Our data indicate that somatic mutations in the TKD of NTRK genes are frequent in LCNECs. Such mutational events could represent an important step in the cancerogenesis of these tumors and may have potential implications for the selection of patients for targeted therapy.
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PMID:Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung. 1829 76

Adult attention deficit hyperactivity disorder (ADHD) is a widely under-reported but nevertheless common condition with a clear heritable component. Several genes have been proposed to play a role in the childhood onset of this neurodevelopmental disorder; however, association studies of persistence of ADHD into adulthood have rarely been performed. Neurotrophic factors (NTFs) are known to be involved in several aspects of neuronal development and neural plasticity in adults. They have also been linked, particularly through brain-derived neurotrophic factor (BDNF) interaction with dopamine transport, to the pathophysiology of ADHD. This study compares the genotypes of six different single nucleotide polymorphisms of genes within the neurotrophin system and their possible association with adult ADHD score in 143 high-risk male subjects referred to a forensic psychiatric unit. The genes included NTF3, NTRK2 (TrkB), NTRK3 (TrkC), BDNF, and p75(NTR). While none of the SNPs showed significant association with ADHD symptoms, one polymorphism within the exon of NTF3 (rs6332) showed a trend toward an association between the A-allele and increased scores using both the retrospective childhood analysis Wender-Utah Rating Scale (WURS-k) (P = 0.05) and the adult ADHD assessment Wender-Reimherr interview (P = 0.03). This SNP is a silent mutation which might be in linkage disequilibrium with a functional risk variant for ADHD. As the association was only suggestive, however, this finding needs replication in a larger study with higher power.
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PMID:Neurotrophic factor-related gene polymorphisms and adult attention deficit hyperactivity disorder (ADHD) score in a high-risk male population. 1842 17

Increasing evidence suggests a role for nerve growth factor (NGFB), brain-derived neurotrophic factor (BDNF), and their receptors, nerve growth factor receptor (NGFR), and neurotrophin tyrosine kinase receptors 1 and 2 (NTRK1 and NTRK2), in Alzheimer's disease (AD). However, genetic association between the neurotrophin system genes and AD has been poorly investigated. We genotyped 21 single nucleotide polymorphisms (SNPs) within these genes in a population of Italian AD patients and healthy controls. We found an allele-wise association of rs2072446 on NGFR with familial AD (fAD, p = 0.047), and a genotype-wise association of rs2289656 on NTRK2 with sporadic AD (sAD, p = 0.0036). rs6336 on NTRK1 resulted associated to early-onset sAD in both allele-wise (p = 0.028) and genotype-wise (p = 0.014) analysis, while rs1048218 on BDNF showed allele-wise association with late-onset sAD (p = 0.047). A trend to association with sAD and/or fAD was observed for other SNPs. Our results suggest that genetic variants of neurotrophin system genes might confer susceptibility to AD.
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PMID:SNPs in neurotrophin system genes and Alzheimer's disease in an Italian population. 1878 Sep 67


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