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: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. 747 23

Point mutations, deletions, and recombinations of the RET proto-oncogene are associated with several inherited human diseases of neural crest-derived cells: Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is restricted to normal and malignant cells of neural crest origin, such as human neuroblastoma cells. To better understand the role of the activated RET oncogene in neural crest cells, we transfected two adherent human neuroblastoma tumor cell lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell lines overexpressing MEN2B RET demonstrated a marked increase in the cell fraction growing in suspension. Both control and MEN2B cells formed tumors at the site of injection in all cases. However, mice injected with MEN2B cells developed lung metastases at a much higher frequency than control mice. Only RET protein derived from MEN2A transfectant cells had increased autokinase activity, whereas MEN2B transfectant cells demonstrated selective activation of the mitogen-activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a biochemical signaling pathway that may link oncogenic RET with the metastatic process.
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PMID:Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun kinase. 939 66

The receptor tyrosine kinase RET is expressed in a number of neuroblastoma tissues and cell lines, but its role in neuroblastoma remains to be determined. In this study, we examined the roles of RET protein in neuroblastoma by the RNA interference technique using the NB-39-nu neuroblastoma cell line. NB-39-nu neuroblastoma cells show high expression and elevated tyrosine phosphorylation of RET, although short interfering RNA against RET (RET siRNA) did not significantly inhibit cell proliferation or suppression of basal levels of phosphorylation of extracellular regulated kinase (ERK)1/2 or protein kinase B (AKT). By the addition of glial cell line-derived neurotrophic factor (GDNF), both the expression and phosphorylation of RET and the phosphorylation of ERK1/2 and AKT were further increased, whereas cell proliferation was not stimulated under normal culture conditions. However, proliferation of cells cultured under non-adherent conditions was significantly increased by GDNF. The increased proliferation was suppressed by RET siRNA, which also caused inhibition of the phosphorylation of ERK1/2 and AKT. These results suggest that RET signaling plays an important role in GDNF-induced enhancement of non-adherent proliferation of NB-39-nu cells, which might contribute to the metastasis of neuroblastoma.
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PMID:RET protein promotes non-adherent growth of NB-39-nu neuroblastoma cell line. 1932 Jun 41

Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alk^mut tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/Ret^M919T tumors exhibit histological features and expression profiles close to MYCN/Alk^mut tumors. We show that RET transcript levels decrease precedes RET protein levels decrease upon ALK inhibition in neuroblastoma cell lines. Etv5 was identified as a candidate transcription factor regulating Ret expression from murine MYCN/Alk^mut tumor transcriptomic data. We demonstrate that ETV5 is regulated both at the protein and mRNA levels upon ALK activation or inhibition in neuroblastoma cell lines and that this regulation precedes RET modulation. We document that ALK activation induces ETV5 protein upregulation through stabilization in a MEK/ERK-dependent manner. We show that RNAi-mediated inhibition of ETV5 decreases RET expression. Reporter assays indicate that ETV5 is able to drive RET gene transcription. ChIP-seq analysis confirmed ETV5 binding on the RET promoter and identified an enhancer upstream of the promoter. Finally, we demonstrate that combining RET and ALK inhibitors reduces tumor growth more efficiently than each single agent in MYCN and Alk^F1178L-driven murine neuroblastoma. Altogether, these results define the ERK-ETV5-RET pathway as a critical axis driving neuroblastoma oncogenesis downstream of activated ALK.
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PMID:Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis. 2932 60

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