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 doma in. Recent work suggests that APP-BP1 participates in a novel ubiquitinylat ion-related pathway involving the ubiquitin-like molecule NEDD8. We show he re that, in vivo in mammalian cells, APP-BP1 interacts with hUba3, its pres umptive partner in the NEDD8 activation pathway, and that the APP-BP1 bindi ng site for hUba3 is within amino acids 443-479. We also provide evidence t hat the human APP-BP1 molecule can rescue the ts41 mutation in Chinese hams ter 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 tha t this function requires both hUba3 and hUbc12. Overexpression of APP-BP1 i n primary neurons causes apoptosis via the same pathway. A specific caspase -6 inhibitor blocks this apoptosis. These findings are discussed in the con text of abnormalities in the cell cycle that have been observed in Alzheime r's disease.