Abstract
The amyloid precursor protein (APP) has been suggested to regulate gene expression. GeneChip® analysis and in vitro kinase assays revealed potent APP-dependent repression of c-Jun, its target gene SPARC and reduced basal c-Jun N-terminal kinase (JNK) activity in PC12 cells overexpressing APP. UV-induced activation of the JNK signalling pathway and subsequent apoptosis were likewise reduced by APP and this effect could be mimicked by the indirect JNK inhibitor CEP-11004. Treatment with a B⃗-secretase inhibitor did not affect APP-mediated downmodulation of the JNK signalling pathway, suggesting that the effects might be mediated via α-secretase processing of APP. In support of these data, overexpression of the Swedish mutant of APP did not inhibit SPARC expression, UV-induced JNK activation and cell death. Our data suggest an important physiological role of APP and α-secretase activity in the control of JNK/c-Jun signalling, target gene expression and cell death activation in response to cytotoxic stress.
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Abbreviations
- AD:
-
Alzheimer's disease
- AICD:
-
APP intracellular domain
- AP-1:
-
activator protein-1
- APP:
-
amyloid precursor protein
- ECM:
-
extracellular matrix
- JIP-1b:
-
c-Jun N-terminal kinase (JNK)-interacting protein-1b
- JNK:
-
c-Jun N-terminal kinase
- MLK:
-
mixed-lineage kinase
- MnSOD:
-
manganese superoxide dismutase
- NF-κB:
-
nuclear factor-kappa B
- SPARC:
-
secreted protein, acidic and rich in cysteine
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Acknowledgements
We thank Hanni Bähler, Petra Mech, Christiane Schettler and Hildegard Schweers for technical assistance, Drs. Christian Haass and Anne Eckert for cell lines, Drs. Stephen P Trusko and Marcel Leist for CEP-11004 and Dr. Kirsten Mielke for helpful discussions. This work was supported by grants from Alzheimer Forschung Initiative e.V. to DK (AFI Grant 03809) and JHMP (AFI Grant 00808), as well as Science Foundation Ireland (03/RP1/B344) and Interdisciplinary Center for Clinical Research (IZKF), University of Münster (Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie Grant 01 KS 9604/0) to JHMP.
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Kögel, D., Schomburg, R., Copanaki, E. et al. Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway. Cell Death Differ 12, 1–9 (2005). https://doi.org/10.1038/sj.cdd.4401495
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DOI: https://doi.org/10.1038/sj.cdd.4401495
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