RESUMO
Presenilin 1 (PS1) plays a pivotal role in Notch signaling and the intracellular metabolism of the amyloid beta-protein. To understand intracellular signaling events downstream of PS1, we investigated in this study the action of PS1 on mitogen-activated protein kinase pathways. Overexpressed PS1 suppressed the stress-induced stimulation of stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) in human embryonic kidney 293 cells. Interestingly, two functionally inactive PS1 mutants, PS1(D257A) and PS1(D385A), failed to inhibit UV-stimulated SAPK/JNK. Furthermore, H(2)O(2-) or UV-stimulated SAPK activity was higher in mouse embryonic fibroblast (MEF) cells from PS1-null mice than in MEF cells from PS(+/+) mice. MEF(PS1(-/-)) cells were more sensitive to the H(2)O(2)-induced apoptosis than MEF(PS1(+/+)) cells. Ectopic expression of PS1 in MEF(PS1(-/-)) cells suppressed H(2)O(2)-stimulated SAPK/JNK activity and apoptotic cell death. Together, our data suggest that PS1 inhibits the stress-activated signaling by suppressing the SAPK/JNK pathway.
Assuntos
Proteínas de Membrana/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Humanos , Peróxido de Hidrogênio/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas de Membrana/genética , Camundongos , Camundongos Mutantes , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neuroblastoma/metabolismo , Presenilina-1 , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Raios Ultravioleta/efeitos adversosRESUMO
The role of PKC epsilon in amyloid precursor protein (APP) processing was investigated using APP-overexpressing B103 cells. As reported previously, a PKC activator, phorbol-12,13-dibutyrate (PDBu), enhanced secretion of APP alpha, and this effect was blocked by a PKC inhibitor, GF109203X in this system. Selective inhibition of PKC epsilon by overexpressing the PKC epsilon V1 region, which binds specifically to the receptor for activated C-kinase (RACK), blocked PDBu-induced enhancement of APP alpha secretion as well as PDBu-induced decrease in beta-secretase-derived APP C-terminal fragment production. On the other hand, the level of PKC epsilon, but not that of PKC alpha or PKC gamma, was substantially lower in the brains of Alzheimer's disease patients compared to age-matched controls. These results add to a growing body of evidence that PKC epsilon plays an important role in modulating APP processing, and suggest that reduced PKC epsilon activity may contribute to the development of Alzheimer's disease.