Journal
CELL DEATH & DISEASE
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2014.196
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Funding
- National Basic Research Program of China (973 Program) [2010CB944901, 2011CB943903]
- National Natural Science Foundation of China [31071294, 31171413, 31371490]
- PhD Programs Foundation of Ministry of Education of China [20120072120030]
- Shanghai Committee of Science and Technology [09DZ2260100]
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The amyloid precursor protein (APP) is a broadly expressed transmembrane protein that has a significant role in the pathogenesis of Alzheimer's disease (AD). APP can be cleaved at multiple sites to generate a series of fragments including the amyloid beta (A beta) peptides and APP intracellular domain (AICD). Although A beta peptides have been proposed to be the main cause of AD pathogenesis, the role of AICD has been underappreciated. Here we report that APP induces AICD-dependent cell death in Drosophila neuronal and non-neuronal tissues. Our genetic screen identified the transcription factor forkhead box O (FoxO) as a crucial downstream mediator of APP-induced cell death and locomotion defect. In mammalian cells, AICD physically interacts with FoxO in the cytoplasm, translocates with FoxO into the nucleus upon oxidative stress, and promotes FoxO-induced transcription of pro-apoptotic gene Bim. These data demonstrate that APP modulates FoxO-mediated cell death through AICD, which acts as a transcriptional co-activator of FoxO.
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