ABSTRACT
Glial cell line-derived neurotrophic factor (GDNF) is considered to be involved in the development of glioma. However, uncovering the underlying mechanism of the proliferation of glioma cells is a challenging work in progress. We have identified the binding of the precursor of N-cadherin (proN-cadherin) and GDNF on the cell membrane in previous studies. In the present study, we observed increased U251 Malignant glioma (U251MG) cell viability by exogenous GDNF (50 ng/ml). We also confirmed that the high expression of the proN-cadherin was stimulated by exogenous GDNF. Concurrently, we affirmed that lower expression of proN-cadherin correlated with reduced glioma cell viability. Additionally, we observed glioma cell U251MG viability as the phosphorylation level of FGFR1 at Y653 and Y654 was increased after exogenous GDNF treatment, which led to increased interaction between proN-cadherin and FGFR1 (pY653+Y654). Our experiments presented a new mechanism adopted by GDNF supporting glioma development and indicated a possible therapeutic potential via the inhibition of proN-cadherin/FGFR1 interaction.
Subject(s)
Antigens, CD/genetics , Cadherins/genetics , Glial Cell Line-Derived Neurotrophic Factor/genetics , Glioma/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell Survival/genetics , Gene Expression Regulation, Neoplastic , Glioma/pathology , Humans , Phosphorylation , Signal TransductionABSTRACT
Lysophosphatidic acid (LPA), an extracellular signaling molecule, influences diverse biological events, including the pathophysiological process induced after ischemic brain injury. However, the molecular mechanisms mediating the pathological change after ischemic stroke remain elusive. Here we report that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is regulated by LPA during stroke. AEP proteolytically cleaves tau and generates tauN368 fragments, triggering neuronal death. Inhibiting the generation of LPA reduces the expression of AEP and tauN368, and alleviates neuronal cell death. Together, this evidence indicates that the LPA-AEP pathway plays a key role in the pathophysiological process induced after ischemic stroke. Inhibition of LPA could be a useful therapeutic for treating neuronal injury after stroke.
Subject(s)
Cell Death/drug effects , Cysteine Endopeptidases/metabolism , Lysophospholipids/pharmacology , Neurons/drug effects , Reperfusion Injury/pathology , Animals , Brain Ischemia/drug therapy , Brain Ischemia/pathology , Cysteine Endopeptidases/drug effects , Enzyme Activation/drug effects , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/pathology , Injections, Intraventricular , Lysophospholipids/administration & dosage , Male , PC12 Cells , Rats , Rats, Sprague-Dawley , Reperfusion Injury/enzymology , Stroke/drug therapy , Stroke/pathology , tau Proteins/metabolismABSTRACT
OBJECTIVE: To identify a novel human leukocyte antigen (HLA) B allele and explore its family heritage. METHODS: A novel HLA allele was suspected upon routine HLA typing using a polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) assay. The sequence was confirmed with DNA sequencing and compared with its closest matching allele, B*55:02. The family was also investigated. RESULTS: An unusual reaction pattern was detected during routine HLA typing. The sequence was confirmed to be a novel HLA-B allele, which differed from the closest matching allele, B*55:02 in 7 nt positions in exon 2. Among the 7 mutations from 6 codons, there were two amino acids changes including 69GluâMet and 70GluâAla. CONCLUSION: A novel HLA-B allele has been identified and officially named as B*55:35 by the WHO Nomenclature Committee for Factors of the HLA System (GenBank accession number FJ898284).