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- W3022602643 abstract "Mutations in Presenilins (PS: PS1 and PS2) cause the majority of cases of early–onset familial Alzheimer's disease. PS are components of the γ–secretase complex, which mediates the proteolysis of type I transmembrane proteins including APP and Notch. Several studies in PS1 knockout cultured cells and mice suggest a role of PS1 in cell proliferation. Thus, fibroblasts derived from PS1 knockout mice show increased proliferation compared with control fibroblasts. Due to the involvement of the epidermal growth factor (EGF) receptor in cell growth we analyzed the role of PS in EGF receptor signaling. The aim of this study is to elucidate the role of PS on cell proliferation mediated by the EGF receptor pathway. In the present study we assessed the proliferation rate of control and PS–deficient (PS–/–) mouse embryonic fibroblasts for 0–72 h. To study the activation of the EGF receptor pathway, control and PS–/– fibroblasts were serum–starved and incubated with EGF. Cell lysates were resolved by SDS–PAGE and phosphorylated EGF receptor, Raf, MEK1/2 and Erk1/2 were analyzed by Western blotting. The proliferation rate of fibroblasts derived from PS knockout mice was increased compared with control fibroblasts. Enhanced fibroblast proliferation caused by loss of PS was suppressed by incubating with a specific EGF receptor inhibitor. Moreover, EGF treatment in PS –/– cells caused a sustained phosphorylation of EGF receptor, Raf, MEK1/2 and Erk1/2 compared with control cells. The role of a γ–secretase inhibitor on EGF receptor downstream effectors was also analyzed. The sustained activation of EGF receptor signaling and increased cell number caused by loss of PS suggest that presenilin acts as a negative regulator of the EGF receptor pathway. Current studies are designed to discern the molecular mechanisms regulated by PS on EGF receptor pathway." @default.
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- W3022602643 date "2006-07-01" @default.
- W3022602643 modified "2023-09-27" @default.
- W3022602643 title "P3-411: Presenilin regulates EGF receptor-mediated signaling" @default.
- W3022602643 doi "https://doi.org/10.1016/j.jalz.2006.05.1682" @default.
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