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|Title:||Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells||Authors:||Wang, Lei||Keywords:||DRNTU::Science::Biological sciences::Molecular biology||Issue Date:||2013||Source:||Wang, L. (2013). Molecular mechanisms underlying the neuroprotective effect of IGF-1 in neuroblastoma cells and the pro-metastatic effect of Dph3 in murine melanoma cells. Doctoral thesis, Nanyang Technological University, Singapore.||Abstract:||Parkinson’s disease (PD) is mainly caused by the lost of dopaminergic neurons located in the substantia nigra pars compacta (SNpc). Thus, preventing the death of dopaminergic neurons is thought to be a potential strategy to interfere with the development of PD. The involvement of IGF-1 signaling pathways in neuronal cell survival has been identified in many cell types, but its downstream targets are frequently cell type-specific. In the present work, we studied the effect of IGF-1 on MPP+-induced apoptosis in human dopaminergic neuroblastoma SH-EP1 cells. We found that IGF-1 effectively protects SH-EP1 cells against MPP+-induced apoptotic cell death. We further delineated the underlying molecular mechanism and showed the PI3K/AKT pathway plays a central role in IGF-mediated cell survival against MPP+ neurotoxicity, not the mitogen-activated protein kinase (MAPK)/ERK pathway. Moreover, we demonstrated that the protective effect of AKT is largely dependent on the inactivation of glycogen synthase kinase 3β (GSK-3β), since inhibition of GSK-3β by its inhibitor, BIO, could mimic the protective effect of IGF-1 on MPP+-induced cell death in SH-EP1 cells. Interestingly, the IGF-1 potentiated PI3K/AKT activity is found to negatively regulate the c-Jun N-terminal protein kinase (JNK) related apoptotic pathway and this negative regulation is further shown to be mediated by AKT-dependent GSK-3β inactivation. Thus, our findings may provide a better understanding of the neuroprotective mechanism of IGF-1 on dopaminergic neuronal cell death and could hold tremendous implication for the development of therapy to arrest the progression of PD in the future.||URI:||https://hdl.handle.net/10356/54698||DOI:||10.32657/10356/54698||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Theses|
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Updated on Apr 11, 2021
Updated on Apr 11, 2021
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