The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons.
APP-BP1 binds to the amyloid precursor protein (APP) carboxyl-terminal domain. Recent work suggests that APP-BP1 participates in a novel ubiquitinylation-related pathway involving the ubiquitin-like molecule NEDD8. We show here that, in vivo in mammalian cells, APP-BP1 interacts with hUba3, its presumptive partner in the NEDD8 activation pathway, and that the APP-BP1 binding site for hUba3 is within amino acids 443-479. We also provide evidence that the human APP-BP1 molecule can rescue the ts41 mutation in Chinese hamster cells. This mutation previously has been shown to lead to successive S phases of the cell cycle without intervening G(2), M, and G(1), suggesting that the product of this gene negatively regulates entry into the S phase and positively regulates entry into mitosis. We show that expression of APP-BP1 in ts41 cells drives the cell cycle through the S-M checkpoint and that this function requires both hUba3 and hUbc12. Overexpression of APP-BP1 in primary neurons causes apoptosis via the same pathway. A specific caspase-6 inhibitor blocks this apoptosis. These findings are discussed in the context of abnormalities in the cell cycle that have been observed in Alzheimer's disease.
Chen
Y
Y
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.
McPhie
D L
DL
Hirschberg
J
J
Neve
R L
RL
D000818:Animals; D006224:Cricetinae; D006801:Humans; D051381:Rats; D000544:Alzheimer Disease / Q000209:etiology; D017209:Apoptosis / Q000502:physiology; D053178:Caspase 6; D061945:Caspase Inhibitors; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005816:Genetic Complementation Test; D008938:Mitosis / Q000502:physiology; D000075687:NEDD8 Protein; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011233:Precipitin Tests; D011485:Protein Binding; D016196:S Phase / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins; D020798:Two-Hybrid System Techniques; D044764:Ubiquitin-Activating Enzymes; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
C505514:CASP6 protein, human; C505518:Casp6 protein, rat; D053178:Caspase 6; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D029701:Saccharomyces cerevisiae Proteins; C491802:NAE protein, human; C112595:UBC12 protein, S cerevisiae; D044764:Ubiquitin-Activating Enzymes; D014452:Ubiquitins