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© The Rockefeller University Press, 0021-9525/1999//121 $5.00
The Journal of Cell Biology, Volume 147, Number 1, , 1999 121-134

Presenilin 1 Suppresses the Function of C-Jun Homodimers via Interaction with Qm/Jif-1

^a Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
^b The Third Department of Internal Medicine, National Defense Medical College, Saitama 359-8513, Japan
^c Department of Biochemistry, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 170-0012, Japan
^d Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama 236, Japan
^e Family Studies Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
^f Department of Neurology, MCP-Hahnemann University, Philadelphia, Pennsylvania 19129
^g Laboratory of Environmental Bioichemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
Department of Neurology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan.81-3-5800-654881-3-3815-5411

okazawa-tky{at}umin.u-tokyo.ac.jp

Presenilin 1 (PS1) is the causative gene for an autosomal dominant familial Alzheimer's disease (AD) mapped to chromosome 14. Here we show that QM/Jun-interacting factor (Jif)-1, a negative regulator of c-Jun, is a candidate to mediate the function of PS1 in the cell. We screened for proteins that bind to PS1 from a human embryonic brain cDNA library using the two-hybrid method and isolated one clone encoding the QM/Jif-1 gene. The binding of QM/Jif-1 to full-length PS1 was confirmed in vitro by pull-down assay, and in vivo by immunoprecipitation assays with human samples, including AD brains. Immunoelectronmicroscopic analysis showed that QM/Jif-1 and PS1 are colocalized at the endoplasmic reticulum, and the nuclear matrix in human brain neurons. Chloramphenicol acetyltransferase assays in F9 cells showed that PS1 suppresses transactivation by c-Jun/c-Jun but not by c-Jun/c-Fos heterodimers, consistent with the reported function of QM/Jif-1. By monitoring fluorescent recombinant protein and by gel mobility shift assays, PS1 was shown to accelerate the translocation of QM from the cytoplasm to the nucleus and to thereby suppress the binding of c-Jun homodimer to 12-O-tetradecanoylphorbol-13- acetate (TPA)-responsive element (TRE). PS1 suppressed c-jun–associated apoptosis by retinoic acid in F9 embryonic carcinoma cells, whereas this suppression of apoptosis is attenuated by mutation in PS1. Collectively, the novel function of PS1 via QM/Jif-1 influences c-jun–mediated transcription and apoptosis.

Key Words: Alzheimer's disease • presenilin-1 • c-jun • cell death • QM/Jif-1

© 1999 The Rockefeller University Press

1.used in this paper: Aβ, β-amyloid; AD, Alzheimer's disease; L, anti-loop antibody; N, anti–NH2-terminal antibody; AP, activated protein; APP, amyloid precursor protein; CAT, chloramphenicol acetyltransferase; EGFP, enhanced green fluorescent protein; GLUT1, glucose transporter 1; GST, glutathione S-transferase; Jif, Jun-interacting factor; JNK, c-Jun NH2-terminal kinase; nt, nucleotide(s); PS1, presenilin 1; RT, reverse transcriptase; TRE, 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element

I. Imafuku and T. Masaki contributed equally to this work.

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