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 t
o mediate the function of PSI in the cell. We screened for proteins that bi
nd to PS1 from a human embryonic brain cDNA library using the two-hybrid me
thod and isolated one clone encoding the QM/Jif-1 gene. The binding of QM/J
if-1 to full-length PS1 was confirmed in vitro by pull-down assay, and in v
ivo by immunoprecipitation assays with human samples, including AD brains.
Immunoelectronmicroscopic analysis showed that QM/Jif-1 and PS1 are colocal
ized at the endoplasmic reticulum, and the nuclear matrix in human brain ne
urons. Chloramphenicol acetyltransferase assays in F9 cells showed that PS1
suppresses transactivation by c-Jun/c-Jun but not by c-Jun/c-Fos heterodim
ers, consistent with the reported function of QM/Jif-1. By monitoring fluor
escent 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-tetradecanoylph
orbol-13-acetate (TPA)-responsive element (TRE). PSI suppressed c-jun-assoc
iated apoptosis by retinoic acid in F9 embryonic carcinoma cells, whereas t
his suppression of apoptosis is attenuated by mutation in PS1. Collectively
, the novel function of PS1 via QM/Jif-1 influences c-jun-mediated transcri
ption and apoptosis.