Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human ret proto-oncogene (proto-ret), encoding a receptor tyrosine kinase, is highly expressed in neuroblastomas, medullary thyroid carcinomas (MTCs) and pheochromocytomas, which are all tumors of cells originating from the neural crest. In studies on the transcription mechanism of proto-ret, we identified the transcription start site and the promoter region by chloramphenicol acetyl transferase (CAT) assay. A sequence upstream from the transcription start site (-167 to +98 bp) showed definite promoter activity in both proto-ret mRNA-positive neuroblastoma NB39-nu cells and proto-ret mRNA-negative HeLa cells. The promoter sequence had a high GC content and contained four tandemly repeated GC boxes without a TATA box. Putative binding sequences for SP-1, AP-2 and epidermal growth factor receptor-specific transcription factor (ETF) and also the transcription-suppressing factor, GC factor (GCF), were found in the repeated GC box region. Southern blot analysis of DNAs of neuroblastoma cell lines and primary MTCs showed that the high proto-ret expression in these tumors is not caused by gross genetic changes in the promoter region, suggesting the possible involvement of a region(s) other than the sequence from -167 to +98 bp or a minor genetic change(s) in the promoter region.
 ...
PMID:Identification and analysis of the ret proto-oncogene promoter region in neuroblastoma cell lines and medullary thyroid carcinomas from MEN2A patients. 135 Jun 70

The RET proto-oncogene, which encodes a receptor tyrosine kinase, displays multiple alternative splicing variants. Splicing of sequences 3' of exon 19 to generate several coding and untranslated region (UTR) sequences has been previously reported. We have sequenced the full length RET coding region and characterized the transcripts and 3' UTRs generated by alternative splicing of the RET 3' terminus. These analyses were performed using both RET cDNA cloned from a pheochromocytoma library and reverse transcriptase PCR products generated using RNA from a neuroblastoma cell line (LA-N-2). Three different carboxyl termini were identified. In addition to the nine and 51 terminal amino acid forms already known, we identified a third with 43 terminal amino acids predicted to encode a novel RET protein isoform. A total of 3621 base pairs of DNA 3' of exon 19, which spans the alternatively spliced exons and RET UTRs, was sequenced. Four polyadenylation sites were identified. The observed combinations of polyadenylation sites and 3' coding sequence suggest that RET transcripts with up to 10 different 3' sequences and up to 40 different full length RET transcripts may exist.
 ...
PMID:Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. 747 23

We previously identified a human cDNA encoding a novel receptor tyrosine kinase, termed Sky, which is predominantly expressed in the brain and has a unique extracellular domain consisting of two immunoglobulin (Ig)-like and two fibronectin type III (FN III) motifs. In attempts to define the functional role of the Sky receptor, we cloned a rat sky cDNA, and localized the sites of expression of sky transcript in the adult rat brain by Northern blot and in situ hybridization analyses using the cloned rat cDNA as a probe. The deduced amino acid sequence of rat Sky has an overall sequence and a domain topology highly conserved with human Sky (90% overall identity and 98% identity within the tyrosine kinase domain). Northern blot analysis revealed that a single 3.8-kb sky mRNA is expressed in PC12 pheochromocytoma and Neuro-2a neuroblastoma cell lines and in various regions of the adult rat brain. In situ hybridization analysis revealed widespread but confined neuronal populations in adult rat brain that express sky transcript; prominent hybridization signals were detected in the inner granular layer of the olfactory bulb, CA-1 area of the hippocampus, granule cell layer of the cerebellum, tenia tectum and cingulate gyrus neurons, and wide regions of cortex layers II-VI. The high level of expression of sky mRNA in neurons in restricted brain regions suggests that the Sky receptor may play an important role in development, function, and maintenance of specific neuronal populations in the central nervous system.
 ...
PMID:Molecular cloning and in situ localization in the brain of rat sky receptor tyrosine kinase. 749 Feb 70

Nerve growth factor (NGF) binds to two distinct cell surface receptors, TrkA, which is a receptor tyrosine kinase, and p75NGFR, whose role in NGF-induced signal transduction remains unclear. We have found that human neuroblastoma IMR-32 cells express TrkA, but p75NGFR expression was not detectable in these cells by northern blot analysis, immunoblotting, or chemical crosslinking experiments. Despite the lack of p75NGFR expression, subnanomolar concentrations of recombinant human NGF induced neurite outgrowth, tyrosine phosphorylation, and immediate early gene expression in these cells. These results strongly suggest that NGF-induced neuronal differentiation in IMR-32 cells is initiated through TrkA in the absence of p75NGFR. Thus, IMR-32 cells may provide a model for studying neurotrophic effects of NGF on adult striatal cholinergic neurons, which also lack p75NGFR expression.
 ...
PMID:Nerve growth factor-induced differentiation in neuroblastoma cells expressing TrkA but lacking p75NGFR. 752 88

The RET proto-oncogene encodes a receptor tyrosine kinase expressed during neural crest development. RET expression is enhanced in vitro by several differentiating agents, including retinoic acid (RA), which up-regulates RET expression in neuroblastoma cell lines. In the present work we sequenced and analysed a 5 kbp genomic fragment 5' to RET. Three deletion fragments of this region were tested for their RA inducibility in transient transfection assays and failed to support the hypothesis of a direct transcriptional activation. Finally, our functional analysis of a candidate RA response element present in the RET promoter provides new hints for the understanding of the interaction between nuclear receptors and their specific recognition sites.
 ...
PMID:Sequence and characterisation of the RET proto-oncogene 5' flanking region: analysis of retinoic acid responsiveness at the transcriptional level. 942 23

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) define a new family of neurotrophic factors that play crucial roles in survival and differentiation of various neurons. Recent studies demonstrated that GDNF and NTN use a multicomponent receptor system in which glycosyl-phosphatidylinositol (GPI)-linked cell surface proteins and Ret receptor tyrosine kinase function as the ligand-binding and signalling components, respectively. In the present study, we investigated the role of Ca2+ ions for biochemical and biological activities of Ret because Ret has a unique structure of the extracellular domain with the cadherin-like motif. The results demonstrated that Ca2+ ions might be required for the complex formation of Ret and GDNF or NTN that induces Ret oligomerization and autophosphorylation. Full morphological differentiation of neuroblastoma cells by these neurotrophic factors was also Ca2+-dependent. These findings thus suggested that, in addition to GPI-linked cell surface proteins, Ca2+ ions are components of the signal transducing complex formed by Ret and GDNF protein family.
 ...
PMID:Calcium-dependent Ret activation by GDNF and neurturin. 946 54

Specific germline mutations in the RET proto-oncogene predispose to the familial cancer syndromes: multiple endocrine neoplasia (MEN) types 2A and 2B, and familial medullary thyroid carcinoma. Expression of the RET receptor tyrosine kinase is tightly restricted to tumours of neural crest origin, such as neuroblastoma, and neuroblastoma has been observed in RET transgenic mice. Neuroblastoma tumour cell lines transfected with the MEN2A RET gene exhibit spontaneous neuritic differentiation, whereas MEN2B-type RET transfectants demonstrate altered cell adhesion and enhanced metastatic potential. In this study, the authors examined genomic DNA from 26 primary neuroblastoma tumours for MEN2A and MEN2B RET mutations, using restriction enzyme digestion of polymerase chain reaction products as an alternative to direct sequencing. Examination of RET exons 10 (codons 611, 618, 620), 11 (codons 632, 633, 634) and 16 (codon 918) in all 26 tumours revealed no RET mutations. Taken together these data suggest that abnormalities of the RET signalling pathway, rather than oncogenic, MEN2-type RET activation by mutation, may play a role in neuroblastoma tumorigenesis.
 ...
PMID:Absence of MEN2A- or 2B-type RET mutations in primary neuroblastoma tumour tissue. 972 1

The receptor tyrosine kinase Flt3 is expressed on the blasts of a high proportion of AML cases. We were interested in the expression and function of Flt3 on various human tumors. human tumor cell lines were tested for Flt3 expression by northern blot analysis and RT-PCR using head/neck (n=3), breast (n=4), ovarian (n=4), small cell lung (n=2), non-small cell lung (n=2), gastric (n=1), colon (n=3), pancreatic (n=1) and prostate carcinoma (n=1), choriocarcinoma (n=1), glioblastoma (n=5), neuroblastoma (n=1), melanoma (n=3), lymphoma (n=1), Hodgkin's disease (n=2), and leukemic (n=6) cell lines. With no expression on the other cell samples, 3 of 6 leukemic cell lines showed expression of Flt3 mRNA. The cDNA region corresponding to the juxtamembrane domain did not show any mutation as determined by sequence analysis. In all 3 positive cell lines, protein expression was verified by immunoprecipitation followed by immunoblot analysis. Although Flt3 is functional in these cell lines, as judged by ligand-dependent receptor autophosphorylation, it only mediates a proliferative response in 2 of the 3 cell lines. In conclusion, Flt3 is expressed exclusively in hematopoietic malignancies. Although early signalling events are detectable in all Flt3-positive cell lines tested, the expression of Flt3 does not predict a proliferative response of the cell lines. No internal tandem duplication of the juxtamembrane domain can be observed.
 ...
PMID:Expression and function of Flt3/flk2 in human tumor cell lines. 1008 27

Glial cell line-derived neurotrophic factor (GDNF) signals through a unique receptor system that includes Ret receptor tyrosine kinase and a glycosyl-phosphatidylinositol-linked cell surface protein. In the present study, we have identified several proteins in neuroblastoma cells that are phosphorylated on tyrosine in response to GDNF. The phosphorylated proteins include focal adhesion kinase (FAK), paxillin and Crk-associated substrate, p130Cas, all of which are known to be associated with focal adhesions. Of these, paxillin and p130Cas interacted with Crk proteins in GDNF-treated neuroblastoma cells. GDNF also induced reorganization of the actin cytoskelton. Tyrosine phosphorylation of FAK, paxillin and p130Cas was inhibited by cytochalasin D or two specific inhibitors of phosphatidylinositol-3' kinase (PI-3' kinase), wortmannin and LY294002, indicating that their tyrosine phosphorylation depends on the formation of actin stress fiber and activation of PI-3' kinase. In addition, phosphorylation of FAK but not of paxillin and p130Cas was markedly impaired by the Clostridium botulinum C3 exoenzyme that specifically ADP-ribosylates and inactivates Rho. These results suggested the presence of Rho-dependent and -independent signaling pathways downstream of PI-3' kinase that mediate tyrosine phosphorylation of FAK, paxillin and p130Cas through Ret kinase.
 ...
PMID:Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinase. 1020 19

Receptor-mediated gene transfer is an effective strategy among nonviral vector systems. It is, however, crucial to develop various types of monoclonal antibodies satisfying both the binding specificity for cell targeting and the capacity of endocytosis required for gene transfer. In the present study, we generated a novel monoclonal antibody (NBL-1) to RET, a receptor tyrosine kinase expressed in both neuroblastoma cells and cells present in substantia nigra, a responsive locus of Parkinson's disease. NBL-1, when added to the culture medium of the neuroblastoma cells, was incorporated by endocytosis in a wortmannin-sensitive manner. Using a biotinylated NBL-1 complexed with plasmid DNAs based on electrostatic interaction through avidin-conjugated polylysines, exogenous luciferase genes were expressed in neuroblastoma cells at a more than 10-fold higher level. The expression level of the gene based on NBL-1 was comparable to that obtained by a geneporter system, an improved nonviral gene transduction method. Furthermore, the NBL-1-based gene transfer mediated the formation of more than 20-fold higher numbers of drug-resistant colonies. In contrast, RET-negative cells, which included HeLa, HT1080, Caco-2, and Colo205 cells, did not show any increased expression of an exogenous gene by NBL-1. These data suggest that the RET molecules enable selective gene transduction, and that NBL-1 may possibly be applied to gene therapy for neuroblastomas and Parkinson's disease.
 ...
PMID:Improved gene transfer to neuroblastoma cells by a monoclonal antibody targeting RET, a receptor tyrosine kinase. 1081 Dec 28


1 2 3 4 5 6 7 8 9 10 Next >>