Negative regulation of the SAPK/JNK signaling pathway by presenilin 1

Presenilin 1 (PS1) plays a pivotal role in Notch signaling and the intracellular metabolism of the amyloid β-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 NH₂-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, H₂O₂- 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 H₂O₂-induced apoptosis than MEF^PS1(+/+) cells. Ectopic expression of PS1 in MEF^PS1(-/-) cells suppressed H₂O₂-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.