JNK-interacting protein-1 promotes transcription of A beta protein precursor but not A beta precursor-like proteins, mechanistically different than Fe65.
Processing of the amyloid beta protein precursor (A beta PP) by the beta and gamma secretases leads to the production of two small peptides, amyloid beta and the A beta PP intracellular domain (AID, or called elsewhere AICD). Whereas the role of amyloid beta in the pathogenesis of Alzheimer's disease has been studied extensively, only recently has information begun to accumulate as to the role of AID. Functions identified for AID include its ability to trigger apoptosis and a role in regulating gene transcription, particularly in combination with the A beta PP binding protein Fe65. Here, we report that AID in combination with Janus kinase interacting protein-1 (JIP-1) can activate gene expression. We demonstrate that the mechanism is different from activation in combination with Fe65 by first showing that although Fe65 enters the nucleus in the absence of full-length A beta PP, JIP-1 does not. Additionally, JIP-1-induced activation is Tip60 independent, whereas a complex with AID, Fe65, and Tip60 is formed for Fe65-induced activation. Finally, and probably most interestingly, we show that although the A beta PP family members APLP1 and APLP2 (for amyloid beta precursor-like protein) can cause activation in combination with Fe65, APLP1 and APLP2 show little or no activation in combination with JIP-1. This activity for the AID fragment may help explain the unique functions of A beta PP relative to its other family members, and changes in gene expression found in Alzheimer's disease.
Scheinfeld
Meir H
MH
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Matsuda
Shuji
S
D'Adamio
Luciano
L
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
C091042:APBB1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; C490666:MAPK8IP1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins