title: Presenilin 1 mediates retinoic acid-induced differentiation of SH-SY5Y cells through facilitation of Wnt signaling.
abstract: Presenilin 1 interacts with beta-catenin, an essential component of the Wnt signaling pathway. To elucidate the role of presenilin 1-beta-catenin interaction in neuronal differentiation, we established SH-SY5Y cells stably expressing wild-type presenilin 1, P117L mutant presenilin 1, which is linked to the early-onset familial form of Alzheimer's disease, and D385A mutant presenilin 1, which has no aspartyl proteinase activity. We demonstrate that SH-SY5Y cells stably expressing D385A mutant presenilin 1 failed to differentiate in response to retinoic acid treatment. Retinoic acid caused an increase in nuclear beta-catenin levels in SH-SY5Y cells, which was followed by an increase in cyclin D1 protein levels. Abnormal cellular accumulation of beta-catenin was observed in D385A mutant transfected cells, whereas nuclear beta-catenin and cellular cyclin D1 levels failed to increase. Conversely, SH-SY5Y cells expressing the P117L mutant differentiated normally and showed increased nuclear beta-catenin and cellular cyclin D1 levels. These findings suggest that neuronal differentiation of SH-SY5Y cells involves the Wnt signaling pathway and that presenilin 1 plays a crucial role in Wnt signal transduction by regulating the nuclear translocation of beta-catenin.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kitagawa
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kohno
authors.forename: Akira
authors.initials: A
authors.lastname: Kuzuya
authors.forename: Takashi
authors.initials: T
authors.lastname: Kageyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibasaki
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation / Q000187:drug effects / Q000502:physiology; D053764:Presenilin-1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D014212:Tretinoin