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)

Neuroblastomas often undergo spontaneous differentiation and/or regression in vivo, which is at least partly regulated by the signals through neurotrophins and their receptors. Recently, glial cell line-derived neurotrophic factor (GDNF) and a second family member, neurturin (NTN), have been found to mediate their signals by binding to a heterotetrameric complex of c-Ret tyrosine kinase receptors and glycosylphosphatidylinositol-linked proteins, GFR alpha-1 (GDNFR-alpha) or GFR alpha-2 (TrnR2/GDNFR-beta/NTNR-alpha/RETL2). Here, we studied the effect of GDNF and NTN on human neuroblastomas in the short-term primary culture system, as well as the expression of c-Ret, GFR alpha-1, GFR alpha-2, GDNF, and NTN. GDNF (1-100 ng/ml) induced morphological differentiation in 34 of 38 primary neuroblastomas and an accompanying increase in c-Fos induction. These effects were markedly enhanced by treatment with 5 microM all-trans-retinoic acid. Although GDNF alone induced a rather weak differentiation independent of the disease stages, the enhancement of neurite outgrowth induced by treatment with both GDNF and all-trans-retinoic acid was significantly correlated with younger age (less than 1 year; P = 0.0039), non-stage 4 diseases (P = 0.0023), a single copy of N-myc (P = 0.027), and high levels of TRK-A expression (P = 0.0062). To examine the expression levels of GFR alpha-1, we cloned a short form of the human GFR alpha-1 gene with a 15-bp deletion by screening a human adult substantia nigra cDNA library. Many primary neuroblastomas expressed c-Ret, GFR alpha-1, and GFR alpha-2 as well as their ligands, GDNF and NTN, suggesting the presence of a paracrine or autocrine signaling system within the tumor tissue. The effect of NTN on primary culture cells of neuroblastoma was similar to that of GDNF. These imply that the GDNF(NTN)/c-Ret/GFR alpha-1(GFR alpha-2) signaling may have an important role in regulating the growth, differentiation, and cell death of neuroblastomas.
 ...
PMID:Glial cell line-derived neurotrophic factor/neurturin-induced differentiation and its enhancement by retinoic acid in primary human neuroblastomas expressing c-Ret, GFR alpha-1, and GFR alpha-2. 960 60

Neuroblastoma is a childhood tumor, and high-stage neuroblastoma has a poor prognosis. The regulatory mechanisms for neuroblastoma progression are poorly understood. In present study, we found that GDNF family receptor alpha 2 (GFRA2) was upregulated in neuroblastoma cells and tissues, and its overexpression promoted neuroblastoma cell proliferation, as revealed using colony formation, soft agar growth, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays Tumor suppressor phosphatase and tensin homolog (PTEN) is an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway that interacts with GFRA2. A luciferase activity assay showed GFRA2 inhibits the transcriptional activity of the forkhead box O (FOXO) family proteins, which suggested that GFRA2 activated the PI3K/AKT pathway. Inhibition of the PI3K/AKT pathway in GFRA2 overexpressing cells decreased cell proliferation, confirming that GFRA2 promoted neuroblastoma cell proliferation by activating the PI3K/AKT pathway. In summary, cell proliferation via the GFRA2-PTEN-PI3K/AKT axis may represent new target to develop treatments for neuroblastoma.
 ...
PMID:GDNF family receptor alpha 2 promotes neuroblastoma cell proliferation by interacting with PTEN. 3072 93