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

Imafuku I, Masaki T, Waragai M, Takeuchi S, Kawabata M, Hirai S, Ohno S, Nee LE, Lippa CF, Kanazawa I, Imagawa M, Okazawa H - J. Cell Biol. (1999)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

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.

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Northern blot analyses of the QM expression in various organs and various regions of the brain. PS309-4 cDNA was used as the probe. The final wash was 0.1× SSC/0.1% SDS at 60°C for 60 min. nucl, nucleus.
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Figure 3: Northern blot analyses of the QM expression in various organs and various regions of the brain. PS309-4 cDNA was used as the probe. The final wash was 0.1× SSC/0.1% SDS at 60°C for 60 min. nucl, nucleus.

Mentions: To observe the interaction between QM and PS1 in the brain morphologically, we performed immunohistochemical analyses. As QM expression has not been reported previously, we confirmed that the QM message is widely expressed in the brain by Northern blot analysis (Fig. 3). At the light microscopic level, anti-QM polyclonal antibody stained the cytoplasm of neurons in the mouse cerebral cortex (Fig. 4 a). To further characterize subcellular localization of the QM protein, we observed the mouse brain sample with electronmicroscopy and found that regions very close to tubular membrane structures, which possessed features of smooth endoplasmic reticulum, were predominantly stained (Fig. 4b and Fig. c). This subcellular localization of QM was exactly like that of PS1 reported to date (Lah et al. 1997).


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

Imafuku I, Masaki T, Waragai M, Takeuchi S, Kawabata M, Hirai S, Ohno S, Nee LE, Lippa CF, Kanazawa I, Imagawa M, Okazawa H - J. Cell Biol. (1999)

Northern blot analyses of the QM expression in various organs and various regions of the brain. PS309-4 cDNA was used as the probe. The final wash was 0.1× SSC/0.1% SDS at 60°C for 60 min. nucl, nucleus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2164975&req=5

Figure 3: Northern blot analyses of the QM expression in various organs and various regions of the brain. PS309-4 cDNA was used as the probe. The final wash was 0.1× SSC/0.1% SDS at 60°C for 60 min. nucl, nucleus.
Mentions: To observe the interaction between QM and PS1 in the brain morphologically, we performed immunohistochemical analyses. As QM expression has not been reported previously, we confirmed that the QM message is widely expressed in the brain by Northern blot analysis (Fig. 3). At the light microscopic level, anti-QM polyclonal antibody stained the cytoplasm of neurons in the mouse cerebral cortex (Fig. 4 a). To further characterize subcellular localization of the QM protein, we observed the mouse brain sample with electronmicroscopy and found that regions very close to tubular membrane structures, which possessed features of smooth endoplasmic reticulum, were predominantly stained (Fig. 4b and Fig. c). This subcellular localization of QM was exactly like that of PS1 reported to date (Lah et al. 1997).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

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.

Show MeSH
Related in: MedlinePlus