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Chen, Y, McPhie, DL, Hirschberg, J and Neve, RL (2000) The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J. Biol. Chem. 275:8929-35


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.




Alzheimer Disease/etiology; Animals; Apoptosis/physiology; Caspase 6; Caspases/antagonists & inhibitors; Cerebral Cortex/cytology; Cricetinae; DNA-Binding Proteins/metabolism; Genetic Complementation Test; Humans; Mitosis/physiology; Neurons/cytology; Neurons/physiology; Precipitin Tests; Protein Binding; Rats; S Phase/physiology; Saccharomyces cerevisiae Proteins; Two-Hybrid System Techniques; Ubiquitin-Activating Enzymes; Ubiquitins/genetics; Ubiquitins/metabolism