Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway.
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 gamma-secretase inhibitor did not affect APP-mediated downmodulation of the JNK signalling pathway, suggesting that the effects might be mediated via alpha-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 alpha-secretase activity in the control of JNK/c-Jun signalling, target gene expression and cell death activation in response to cytotoxic stress.
Kögel
D
D
Experimental Neurosurgery, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe University Clinics, D-60590 Frankfurt, Germany. koegel@em.uni-frankfurt.de
Schomburg
R
R
Copanaki
E
E
Prehn
J H M
JH
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D010450:Endopeptidases; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020411:Oligonucleotide Array Sequence Analysis; D015676:Osteonectin / Q000235:genetics; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014466:Ultraviolet Rays
D016564:Amyloid beta-Protein Precursor; C469298:CEP-11004; D002227:Carbazoles; D007211:Indoles; D015676:Osteonectin; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human