Presenilin 1 suppresses the function of c-Jun homodimers via interaction with QM/Jif-1

J Cell Biol. 1999 Oct 4;147(1):121-34. doi: 10.1083/jcb.147.1.121.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alzheimer Disease / pathology
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Biological Transport
  • Brain / cytology
  • Brain / embryology
  • Brain / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Dimerization
  • Female
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Neurons / metabolism*
  • Presenilin-1
  • Proto-Oncogene Proteins c-jun / antagonists & inhibitors
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Ribosomal Protein L10
  • Ribosomal Proteins*
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Two-Hybrid System Techniques
  • Zinc Fingers

Substances

  • Carrier Proteins
  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • RPL10 protein, human
  • Ribosomal Proteins
  • Rpl10 protein, mouse