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J Biol Chem, Vol. 275, Issue 12, 8929-8935, March 24, 2000

The Amyloid Precursor Protein-binding Protein APP-BP1 Drives the Cell Cycle through the S-M Checkpoint and Causes Apoptosis in Neurons^*

Yuzhi Chen, Donna L. McPhie, Joseph Hirschberg^§, and Rachael L. Neve^¶

From the  Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478 and the ^§ Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel

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 G₂, M, and G₁, 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.

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