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J. Cell Biol. 153 (3): 457-464

Copyright © 2001 by the Rockefeller University Press.

Original Article

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

Jin Woo Kima, Tong-Shin Changa, Ji Eun Leea, Sung-Ho Huha, Seung Woo Yeonb, Wan Seok Yangc, Cheol O. Joec, Inhee Mook-Jungb, Rudolph E. Tanzid, Tae-Wan Kimd, , and Eui-Ju Choia

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


Abstract: 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. MEFPS1(–/–) cells were more sensitive to the H2O2-induced apoptosis than MEFPS1(+/+) cells. Ectopic expression of PS1 in MEFPS1(–/–) 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 • {gamma}-secretase • stress-activated protein kinase

J.W. Kim and T.-S. Chang contributed equally to this work and should be considered co-first authors.

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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