TI  -  <prot>Presenilin 1</prot>  suppresses the function of   <prot>c-Jun</prot>   homodimers via interaction
      with  <prot>QM</prot>/<prot>Jif-1</prot> .
PG  - 121-34
AB  - <prot>Presenilin 1</prot> (<prot>PS1</prot>) is the causative gene for an autosomal dominant
      familial Alzheimer's disease (AD) mapped to chromosome 14. Here we show
      that  <prot>QM</prot>/<prot>Jun-interacting factor (Jif)-1</prot> , a negative regulator of  <prot>c-Jun</prot> , is
      a candidate to mediate the function of <prot>PS1</prot> in the cell. We screened for
      proteins that bind to  <prot>PS1</prot>  from a human embryonic brain cDNA library using
      the two-hybrid method and isolated one clone encoding the  <prot>QM</prot>/<prot>Jif-1</prot>  gene.
      The binding of  <prot>QM</prot>/<prot>Jif-1</prot>  to full-length <prot>PS1</prot>  was confirmed in vitro by
      pull-down assay, and in vivo by immunoprecipitation assays with human
      samples, including AD brains. Immunoelectronmicroscopic analysis showed
      that <prot>QM</prot>/<prot>Jif-1</prot> and <prot>PS1</prot> are colocalized at the endoplasmic reticulum, and
      the nuclear matrix in human brain neurons. Chloramphenicol
      acetyltransferase assays in F9 cells showed that <prot>PS1</prot> suppresses
      transactivation by  <prot>c-Jun</prot> / <prot>c-Jun</prot>  but not by  <prot>c-Jun</prot> / <prot>c-Fos</prot>  heterodimers,
      consistent with the reported function of <prot>QM</prot>/<prot>Jif-1</prot>. By monitoring
      fluorescent recombinant protein and by gel mobility shift assays, <prot>PS1</prot> was
      shown to accelerate the translocation of <prot>QM</prot> from the cytoplasm to the
      nucleus and to thereby suppress the binding of   <prot>c-Jun</prot>   homodimer to
      12-O-tetradecanoylphorbol-13- acetate (TPA)-responsive element (TRE). <prot>PS1</prot>
      suppressed <prot>c-jun</prot>-associated apoptosis by retinoic acid in F9 embryonic
      carcinoma cells, whereas this suppression of apoptosis is attenuated by
      mutation in <prot>PS1</prot>. Collectively, the novel function of <prot>PS1</prot> via <prot>QM</prot>/<prot>Jif-1</prot>
      influences <prot>c-jun</prot>-mediated transcription and apoptosis.
AD  - Department of Neurology, Graduate School of Medicine, University of Tokyo,
