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Results for “Candidate pathways”

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PubMed2001

A genetically engineered influenza A virus with ras-dependent oncolytic properties.

The NS1 protein of influenza virus is a virulence factor that counteracts the PKR-mediated antiviral response by the host. As a consequence, influenza NS1 gene knockout virus delNS1 (an influenza A virus lacking the NS1 open reading frame) fails to replicate in normal cells but produces infectious particles in PKR-deficient cells. Because it is known that oncogenic ras induces an inhibitor of PKR, we addressed the question of whether the delNS1 virus selectively replicates in cells expressing oncogenic ras. We show that upon transfection and expression of oncogenic N-ras, cells become permissive for productive delNS1 virus replication, suggesting that the delNS1 virus has specific oncolytic properties. Viral growth in the oncogenic ras-transfected cells is associated with a reduction of PKR activation during infection. Moreover, treatment of s.c. established N-ras-expressing melanomas in severe combined immunodeficiency mice with the delNS1 virus revealed that this virus has tumor-ablative potentials. The delNS1 virus does not replicate in nonmalignant cell lines such as melanocytes, keratinocytes, or endothelial cells. The apathogenic nature of the delNS1 virus combined with the selective replication properties of this virus in oncogenic ras-expressing cells renders this virus an attractive candidate for the therapy of tumors with an activated ras-signaling pathway.

Animals↗

PubMed2003

Mutations of APC, K-ras, and p53 are associated with specific chromosomal aberrations in colorectal adenocarcinomas.

It is widely accepted that both large-scale chromosomal abnormalities and mutation of specific genes, such as APC, K-ras, and/or p53, occur in the majority of colorectal adenocarcinomas. Whether or not a relationship exists between these different forms of genetic abnormalities was previously unknown. Using comparative genomic hybridization and mutational analysis of APC, K-ras, and p53 to evaluate 50 colorectal adenocarcinomas, we have shown that mutation of p53 is significantly associated with gain of 20q, 13q, and 8q and loss of 18q (P = 0.000, 0.02, 0.044, and 0.001, respectively). Conversely, APC mutation did not associate with any of the above-mentioned aberrations but did associate significantly with gain of 7p (P = 0.01). Gain of chromosomal arm 12p, although a less common aberration, was significantly associated with K-ras mutation (P = 0.011). The associations we have described should refine the search for candidate genes underlying chromosomal aberrations and assist in the definition of distinct pathways in colorectal tumorigenesis.

Adaptor Proteins, Signal Transducing↗

PubMed1989

[Interventional electrophysiology: transcatheter electrical shock ablation for arrhythmias].

Patients with supraventricular or ventricular tachyarrhythmias resistant to antiarrhythmic drugs are candidates for surgical ablation of the bundle of His, and of accessory pathways or ventricular or atrial foci responsible for the arrhythmia. During the past 6 years closed-chest catheter techniques have been devised that allow electrical shock ablation of the atrioventricular junction, accessory pathways, or foci responsible for arrhythmias. The promising results of these ablative procedures (especially of the atrioventricular junction and posteroseptal accessory pathways) justify their trial in suitable patients before cardiac electrosurgery.

Arrhythmias, Cardiac↗

PubMed1998

[Molecular basis of Hirschsprung disease].

Hirschsprung disease (HSCR) is a congenital malformation caused by the absence of ganglion cells in the myenteric and submucosal plexuses of the gut. Recent studies have shown that mutations in the RET, glial-cell-derived neurotrophic factor (GDNF), endothelin-B receptor (EDNRB), endothelin-3 genes are responsible for the occurrence of aganglionosis. Those genes are involved in the development of neural crest derivatives. The RET gene mutation are found in 50% of familial cases and 15% of sporadic cases. The mutations in other genes were found under 10%. In addition to such a low detection rate of the mutations, incomplete penetrance of the mutation was found in all four genes. Those results support multifactorial or polygenic feature of Hirschsprung disease. The additional candidate genes responsible for this disease will be identified along the signaling pathway through RET and EDNRB.

Animals↗

PubMed2001

The histopathological differential diagnosis of gastrointestinal stromal tumours.

Gastrointestinal stromal tumours (GISTs), initially presumed to be of "true" smooth muscle origin, encompass a heterogeneous, and as yet incompletely understood, group of mesenchymal tumours with respect to their origin, cellular differentiation, and prognosis. Cellular morphology ranges from predominantly spindle shaped to epithelioid in character, whereas differentiation pathways, as determined primarily by immunohistochemistry and ultrastructure, can vary from indeterminate to myoid and/or neural. Recent work has indicated that the interstitial cells of Cajal, a complex cellular network postulated to act as pacemaker cells of the gastrointestinal tract, which exhibit both myoid and neural features, could be candidates for tumour histogenesis. This would provide a plausible and attractive explanation for the variable differentiation pathways identified in the GIST category to date. Nevertheless, the occasional but undisputed location of GISTs outside the gastrointestinal tract (omentum, peritoneum, and retroperitoneum) might mitigate against such an origin, and their histogenesis remains open to debate. The c-kit proto-oncogene, encoding a growth factor receptor with tyrosine kinase activity, has been postulated to play an important role in tumorigenesis because "gain of function" mutations in this gene, localised to chromosome 4q11-21, are being increasingly identified in hereditary and sporadic cases. Monoclonal and polyclonal antibodies directed at the c-kit gene product expressed on the cell surface (CD117/c-kit) appear to be increasingly helpful in resolving the histopathological differential diagnosis between GISTs and true gastrointestinal smooth muscle neoplasms, schwannomas, and other far less frequently occurring mesenchymal tumours at this site. Although tumours with a clinically benign course appear to be more common than their malignant counterparts, no specific histological criteria have as yet been identified to enable an unambiguous prediction of biological behaviour. Increasing tumour size and mitotic activity favour aggressive tumour behaviour, whereas the prognostic value of germline and somatic mutations within the c-kit proto-oncogene remains to be elucidated further. It is the aim of this synopsis to highlight the relevant fundamental and diagnostic developments with respect to this complex group of neoplasms.

Biomarkers, Tumor↗

PubMed2004

Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications.

Carcinogenesis is a multistep process characterized by genetic alterations that influence key cellular pathways involved in growth and development. Oncogenes refer to those genes whose alterations cause gain-of-function effects, while tumor suppressor genes cause loss-of-function effects that contribute to the malignant phenotype. The effects of these alterations are complex due to the high number of changes in a typical case of breast cancer and the interactions of the biological pathways involved. This review focuses on the more common abnormalities in oncogenes and tumor suppressor genes in human breast cancer and their known associations with clinical outcome in terms of tumor classification, prognosis, and response to specific therapies. A better understanding of these relationships has led to new therapeutic applications. Agents that target oncogenes and their associated pathways are now in clinical use, with many more undergoing preclinical and clinical testing. The availability of antibodies, small synthetic molecules, cyotokines, gene therapy techniques, and even natural compounds that are screened for specific biological properties has greatly increased the number of candidate drugs. Nevertheless, clinical successes have been limited because of the redundancy of many cancer-related pathways as well as the high degree of variability in genotype and phenotype among individual tumors. Likewise, strategies to replace tumor suppressor gene functions face numerous technical hurdles. This review summarizes the current achievements and future prospects for the therapeutic targeting of oncogenes and tumor suppressor genes and new technology to better classify tumors and accurately predict responses to standard and novel agents.

Breast Neoplasms↗

PubMed2006

The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients.

BACKGROUND AND AIM: Hypercholesterolaemia is a major risk factor for atherosclerosis. Cholesterol is modulated by genetic and environmental factors. An important regulatory pathway is controlled by the sterol-regulatory element-binding proteins (SREBPs) and the SREBP cleavage-activating protein (SCAP). Both SREBP-2 and SCAP are candidates to contribute to the development of atherosclerosis. We investigated the possible effects of the variability of proteins involved in this regulatory pathway on plasma lipids among familial hypercholesterolaemia patients. METHODS AND RESULTS: Single nucleotide polymorphisms (SNPs) in the genes encoding SREBP-2 and SCAP causing amino acid changes at positions 595 (595G/A) and 796 (796I/V), respectively, were genotyped in 801 FH individuals originating from Israel, The Netherlands, and Switzerland. A linear regression model to examine the associations between SREBP-2 and SCAP isoforms and lipid and lipoprotein levels was used. In females, homozygosity either for the SREBP-2-595A or for the SCAP-796I isoform was associated with higher LDL-cholesterol plasma concentrations (14.7 mg/dl and 20.3 mg/dl, respectively). Surprisingly, heterozygosity for the combination SREBP-2-595A/SCAP-796I was associated with a decrease of 30.28 mg/dl in LDL-C (p-value for gene-gene interaction=0.09). No such effect was observed among FH males. Subgroup analysis considering the most frequent (N>/=24) LDL receptor mutations (del191-2, ins313+1-2, C660X, E207K, S285L) revealed further gene-dosage- and gender-dependent effects of the SCAP mutations on LDL-cholesterol concentrations (p=0.0345). These effects were, however, not present when less frequent LDL receptor mutations were investigated. CONCLUSIONS: These results suggest a possible gene-gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. Further investigation is needed to confirm this effect. A study in a larger FH group or in non-FH hypercholesterolaemic subjects may further define the role of this regulatory mechanism in determining plasma lipid concentration.

Atherosclerosis↗

PubMedDate not supplied

No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility.

BACKGROUND: The SEL1L gene is located on human chromosome 14q24.3-31 close to D14S67 which has been previously proposed to be a type 1 diabetes mellitus locus (IDDM11). Sel-1 is a negative regulator of the Notch signalling pathway and SEL1L is selectively expressed in adult pancreas and islets of Langerhans. This suggests that SEL1L may be a candidate gene for IDDM11. METHODS: We have analysed two newly identified CA-repeat polymorphisms within the genomic sequence of the SEL1L locus for association with type 1 diabetes mellitus (T1DM) in 152 Danish T1DM-affected sib-pair families and in 240 Sardinian families (229 simplex and 11 sib-pair families). RESULTS: No evidence for association of the two SEL1L markers with T1DM was observed in either the Danish or the Sardinian families. We have also used allelic sharing methods to analyse linkage with T1DM in the IDDM11 region using the same markers and the Danish collection of affected sib-pair families. No evidence of linkage was observed (Z(max)=0.86). CONCLUSION: Although several lines of evidence suggest that SEL1L might be a candidate for IDDM11-conferred susceptibility to T1DM the present study does not support this hypothesis.

Alleles↗

PubMed2006

Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway.

Cutaneous leg ulcers are common in sickle cell anaemia and their risk might be genetically determined. Sickle cell anaemia patients were studied to examine the relationship of leg ulcers with haemolysis and with single nucleotide polymorphisms (SNPs) in candidate genes that could affect sickle vasoocclusion. Leg ulcer patients had lower haemoglobin levels and higher levels of lactate dehydrogenase, bilirubin, aspartate transaminase and reticulocytes than did control patients with sickle cell anaemia but without leg ulcers. Age-adjusted comparisons showed that sickle cell anaemia-alpha thalassaemia was more frequent among controls than cases. These results strongly suggested that the likelihood of having leg ulcers was related to the intensity of haemolysis. 215 SNPs in more than 100 candidate genes were studied. Associations were found with SNPs in Klotho, TEK and several genes in the TGF-beta/BMP signalling pathway by genotypic association analyses. KL directly or indirectly promotes endothelial nitric oxide (NO) production and the TEK receptor tyrosine kinase is involved in angiogenesis. The TGF-beta/BMP signalling pathway modulates wound healing and angiogenesis, among its other functions. Haemolysis-driven phenotypes, such as leg ulcers, could be improved by agents that reduce sickle erythrocyte density or increase NO bioavailability.

Adult↗

PubMed1996

The BAX gene maps to the glioma candidate region at 19q13.3, but is not altered in human gliomas.

The bax protein regulates apoptosis in a cellular pathway that involves both bcl-2 and p53, two molecules associated with human glioma tumorigenesis. We therefore evaluated the possibility that BAX functions as a glioma tumor suppressor gene. Somatic cell hybrid panels, fluorescence in situ hybridization and cosmid mapping localized the BAX gene to 19q13.3, approximately 300 kb centromeric to HRC. Thus BAX maps to the region of chromosome 19 most frequently deleted in gliomas. Routine and pulsed-field gel electrophoresis/Southern blotting studies, however, failed to reveal large-scale deletions or rearrangements of the BAX gene in gliomas. In addition, single strand conformation polymorphism analysis of all six BAX exons and flanking intronic sequences did not disclose mutations in 20 gliomas with allelic loss of the other copy of 19q. A C/T polymorphism was detected in intron 3 and was common in the general population. Therefore, although BAX maps to the glioma candidate region on the long arm of chromosome 19, BAX is probably not the 19q glioma tumor suppressor gene.

Base Sequence↗

PubMed1998

The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose: in search of the underlying mechanism.

By closing ATP-sensitive K+ (K+-ATP) channels, glucose promotes depolarization-dependent Ca2+ entry and cytoplasmic free Ca2+ concentration ([Ca2+]i) rise in beta-cells. Ca2+-dependent exocytosis of insulin granules is then potentiated by a K+-ATP channel-independent action of glucose. The underlying mechanisms of this second pathway are still unclear. They were studied by incubating normal mouse islets in the presence of diazoxide to open K+-ATP channels and 30 mmol/l K+ to restore Ca2+ entry. The effect of glucose did not require priming of beta-cells by preincubation in the presence of high glucose and could not be attributed to interaction of the sugar with a "glucoreceptor." There is no evidence that protein kinases A and C are involved in the K+-ATP channel-independent pathway, because inhibitors of the kinases did not alter the effect of glucose. In 3 mmol/l glucose, fatty acids did not influence K+-induced insulin secretion, even in the presence of bromopalmitate, an inhibitor of fatty acid oxidation. Bromopalmitate alone had no effect, but it decreased the potentiation that the fatty acids produce in 20 mmol/l glucose. It is thus unlikely that long-chain acyl CoAs mediate the effect of glucose. The action of glucose was not associated with an increase in arachidonic acid release from the islets and was not mimicked by exogenous arachidonic acid. Phospholipase A2 inhibitors antagonized the effect of glucose, but their action was not reversed by arachidonic acid or palmitate and was associated with a fall in islet ATP. No evidence could be found for the intervention of NO, cGMP, Mg, phosphate, phosphatidylinositol 3-kinase, or pertussis toxin-sensitive G-proteins. Formycin A, an adenosine analog that is converted to formycin A-triphosphate in islets, increased insulin secretion in the absence and presence of glucose. In conclusion, the present and our previous results strongly suggest that among all known potential second messengers, adenine nucleotides are the best candidates as regulators of insulin secretion through the K+-ATP channel-independent pathway.

Acyl Coenzyme A↗

PubMed2003

Bioinformatic analysis of autism positional candidate genes using biological databases and computational gene network prediction.

Common genetic disorders are believed to arise from the combined effects of multiple inherited genetic variants acting in concert with environmental factors, such that any given DNA sequence variant may have only a marginal effect on disease outcome. As a consequence, the correlation between disease status and any given DNA marker allele in a genomewide linkage study tends to be relatively weak and the implicated regions typically encompass hundreds of positional candidate genes. Therefore, new strategies are needed to parse relatively large sets of 'positional' candidate genes in search of actual disease-related gene variants. Here we use biological databases to identify 383 positional candidate genes predicted by genomewide genetic linkage analysis of a large set of families, each with two or more members diagnosed with autism, or autism spectrum disorder (ASD). Next, we seek to identify a subset of biologically meaningful, high priority candidates. The strategy is to select autism candidate genes based on prior genetic evidence from the allelic association literature to query the known transcripts within the 1-LOD (logarithm of the odds) support interval for each region. We use recently developed bioinformatic programs that automatically search the biological literature to predict pathways of interacting genes (PATHWAYASSIST and GENEWAYS). To identify gene regulatory networks, we search for coexpression between candidate genes and positional candidates. The studies are intended both to inform studies of autism, and to illustrate and explore the increasing potential of bioinformatic approaches as a compliment to linkage analysis.

Autistic Disorder↗

PubMed2026

Nerpa 2: probabilistic linking of biosynthetic gene clusters to nonribosomal peptides.

MOTIVATION: Nonribosomal peptides (NRPs) are bioactive microbial metabolites with high pharmaceutical potential. Although genome mining enables large-scale detection of biosynthetic gene clusters (BGCs) predicted to encode NRPs, reliably linking these clusters to their chemical products remains challenging due to the flexible and heterogeneous organization of NRP assembly pathways. RESULTS: We present Nerpa 2, a probabilistic framework for accurate and scalable linking of NRP BGCs to candidate chemical structures. The method represents assembly lines as hidden Markov models (HMMs) that capture uncertainty and alternative biosynthetic routes. On curated datasets of experimentally validated BGC-product pairs, our tool outperforms existing methods in linking accuracy and pathway reconstruction. When applied to large genome mining datasets, Nerpa 2 efficiently identifies BGCs likely associated with known compounds and highlights potential producers of novel chemistry. AVAILABILITY AND IMPLEMENTATION: Nerpa 2 is freely available at https://github.com/gurevichlab/nerpa.

Multigene Family↗

PubMed1995

Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways.

BACKGROUND: The Ity/Lsh/Bcg gene on mouse chromosome 1 regulates priming/activation of macrophages for antimicrobial and tumouricidal activity. A candidate gene expressed in macrophages has been identified by positional cloning and full-length sequence analysis, and encodes the Natural resistance-associated macrophage protein (Nramp). In this study, we have tested the hypothesis that the Nramp gene corresponds to Ity/Lsh/Bcg. MATERIALS AND METHODS: In vitro transfection was used to introduce the resistant allele into the macrophage cell line RAW 264.7 derived from the recessive susceptible BALB/c mouse strain. Expression of the transgene was monitored on the background of the endogenous susceptible allele by allele-specific oligonucleotide hybridization. RESULTS: Expression of the transgene correlated with three Lshr-associated lipopolysaccharide/interferon-gamma-regulated macrophage activation phenotypes: respiratory burst, nitrite release, and uptake of L-arginine. Endogenous and stimulated L-arginine fluxes were inhibitable with the radical scavengers nordihydroguaiaretic acid and butylated hydroxyanisole. The mitochondrial electron transport inhibitors, rotenone and thenoyltrifluoroacetone, inhibited respiratory burst, and rotenone suppressed L-arginine flux, implying that mitochondrial-derived oxygen radicals are important mediators in Nramp-regulated signal transduction pathways. CONCLUSIONS: These data provide the first direct evidence that Nramp is the product of the Ity/Lsh/Bcg gene, and are consistent with the hypothesis that the many pleiotropic effects of this gene on macrophage activation may all derive from the requirement for mitochondrial generation of oxygen radicals for intracellular signaling.

Animals↗

PubMed1996

Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the drosophila seven in absentia gene.

We report the isolation of 10 differentially expressed cDNAs in the process of apoptosis induced by the p53 tamor suppressor. As a global analytical method, we performed a differential display of mRNA between mouse M1 myeloid leukemia cells and derived clone LTR6 cells, which contain a stably transfected temperature-sensitive mutant of p53. At 32 degrees C wild-type p53 function is activated in LTR6 cells, resulting in programmed cell death. Eight genes are activated (TSAP; tumor suppressor activated pathway), and two are inhibited (TSIP, tumor suppressor inhibited pathway) in their expression. None of the 10 sequences has hitherto been recognized as part of the p53 signaling pathway. Three TSAPs are homologous to known genes. TSAP1 corresponds to phospholipase C beta 4. TSAP2 has a conserved domain homologous to a multiple endocrine neoplasia I (ZFM1) candidate gene. TSAP3 is the mouse homologue of the Drosophila seven in absentia gene. These data provide novel molecules involved in the pathway of wild-type p53 activation. They establish a functional link between a homologue of a conserved developmental Drosophila gene and signal transduction in tumor suppression leading to programmed cell death.

Animals↗

PubMed2004

Positionally cloned susceptibility genes in allergy and asthma.

After several years of research to find asthma-susceptibility genes using genome-wide linkage scans and refined genetic mapping methods, four highly interesting candidate genes have recently been reported. Each of these genes represents a different functional class, and might point to a new pathway in the pathogenesis of asthma. Current research is focusing on confirming the genetic associations in diverse populations and understanding the biochemical functions of the proteins. These second-generation candidate genes for asthma susceptibility will stimulate much research, and might also enable the testing of multigenic models with sufficiently large sample sets.

ADAM Proteins↗

PubMed2006

Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways.

Based on its trophic effects on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of neurodegenerative diseases. To evaluate the therapeutic potential of VEGF, we here examined effects of this growth factor on the degeneration of axotomized retinal ganglion cells (RGCs), which, as CNS-derived neurons, offer themselves in an excellent way to study neuroprotection in vivo. Making use of a transgenic mouse line that constitutively expresses human VEGF under a neuron-specific enolase promoter, we show that (1) the VEGF-transgenic retina overexpresses human VEGF, (2) RGCs carry the VEGF receptor-2, and (3) vascular networks in normal and axotomized VEGF-transgenic (tg) retinas do not differ from control animals. After axotomy, RGCs of VEGF-tg mice were protected against delayed degeneration, as compared with wild-type littermates. Western blots revealed increased phosphorylated ERK-1/2 and Akt and reduced phosphorylated p38 and activated caspase-3 levels in axotomized VEGF-transgenic retinas. Intravitreous injections of pharmacological ERK-1/2 (PD98059) or Akt (LY294002) inhibitors showed that VEGF exerts neuroprotection by dual activation of ERK-1/2 and Akt pathways. In view that axotomy-induced RGC death occurs slowly and considering that RGCs are CNS-derived neurons, we predict the clinical implementation of VEGF in neurodegenerative diseases of both brain and retina.

Animals↗

PubMed2002

Unravelling novel intracellular pathways in cell-based assays.

The pharmaceutical industry is currently facing several challenges to identify and develop novel drug targets. Traditional drug discovery focussed on a small number of well-characterized gene products. Recently, this picture has changed with the completion of the draft sequence of the human genome, which has led to the identification of thousands of novel genes with unknown or poorly understood function. To cope with this overwhelming number of potential drug target candidates, new strategies for the elucidation of gene function, as well as their involvement in intracellular pathways, are required.

Biological Assay↗