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© The Rockefeller University Press, 0021-9525/2001//457 $5.00
The Journal of Cell Biology, Volume 153, Number 3, , 2001 457-464

Negative Regulation of the Sapk/Jnk Signaling Pathway by Presenilin 1

^a National Creative Research Initiative Center for Cell Death, Graduate School of Biotechnology, Korea University, Seoul, 136-701, Korea
^b Brain Disease Research Center, Ajou University School of Medicine, Suwon, Kyongki-do, Korea
^c Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon, 305-701, Korea
^d Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129
National Creative Research Initiative Center for Cell Death, Graduate School of Biotechnology, Korea University, Seoul, 136-701, Korea.82-2-927-902882-2-3290-3446

ejchoi{at}mail.korea.ac.kr

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.

Key Words: apoptosis • c-Jun NH₂-terminal kinase • presenilin 1 • -secretase • stress-activated protein kinase

© 2001 The Rockefeller University Press

T.-W. Kim's present address is Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.

Abbreviations used in this paper: Aβ, amyloid β-peptide; AD, Alzheimer's disease; APP, amyloid β-protein precursor; Erk, extracellular signal-regulated kinase; FAD, familial AD; HA, hemagglutinin; HEK, human embryonic kidney; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MEF, mouse embryonic fibroblast; PS1 and PS2, presenilins 1 and 2; SAPK, stress-activated protein kinase.

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