期刊
CELL DEATH AND DIFFERENTIATION
卷 12, 期 1, 页码 1-9出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401495
关键词
microarray analysis; ultraviolet (UV) irradiation; apoptosis; caspases
The amyloid precursor protein (APP) has been suggested to regulate gene expression. GeneChip(R) 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.
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