Up-regulation of Functionally Impaired Insulin-like Growth Factor-1 Receptor in Scrapie-infected Neuroblastoma Cells

• Published in: The Journal of biological chemistry 2001-09, Vol.276 (39), p.36110-36115
• Main Authors: Östlund, Pernilla, Lindegren, Heléne, Pettersson, Christina, Bedecs, Katarina
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Brain Neoplasms - metabolism; Cell Division; Coculture Techniques; Dose-Response Relationship, Drug; Humans; Kinetics; Mice; NATURAL SCIENCES; NATURVETENSKAP; Neuroblastoma - metabolism; Phosphorylation; Precipitin Tests; Protein Binding; Receptor, IGF Type 1 - chemistry; Receptor, IGF Type 1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Scrapie - metabolism; Time Factors; Tumor Cells, Cultured; Tyrosine - metabolism; Up-Regulation
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M105710200

A growing body of evidence suggests that an altered level or function of the neurotrophic insulin-like growth factor-1 receptor (IGF-1R), which supports neuronal survival, may underlie neurodegeneration. This study has focused on the expression and function of the IGF-1R in scrapie-infected neuroblastoma cell lines. Our results show that scrapie infection induces a 4-fold increase in the level of IGF-1R in two independently scrapie-infected neuroblastomas, ScN2a and ScN1E-115 cells, and that the increased IGF-1R level was accompanied by increased IGF-1R mRNA levels. In contrast to the elevated IGF-1R expression in ScN2a, receptor binding studies revealed an 80% decrease in specific125I-IGF-1-binding sites compared with N2a cells. This decrease in IGF-1R-binding sites was shown to be caused by a 7-fold decrease in IGF-1R affinity. Furthermore, ScN2a showed no significant difference in IGF-1 induced proliferative response, despite the noticeable elevated IGF-1R expression, putatively explained by the reduced IGF-1R binding affinity. Additionally, IGF-1 stimulated IGF-1Rβ tyrosine phosphorylation showed no major change in the dose-response between the cell types, possibly due to altered tyrosine kinase signaling in scrapie-infected neuroblastoma cells. Altogether these data indicate that scrapie infection affects the expression, binding affinity, and signal transduction mediated by the IGF-1R in neuroblastoma cells. Altered IGF-1R expression and function may weaken the trophic support in scrapie-infected neurons and thereby contribute to neurodegeneration in prion diseases.