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PMID:10722740

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Citation

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

Abstract

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.

Links

PubMed

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ULA1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8TBC4

F

Seeded From UniProt

complete

HUMAN:ULA1

involved_in

GO:0033314: mitotic DNA replication checkpoint signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBA3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13564

F

Seeded From UniProt

complete

HUMAN:ULA1

GO:0042981 : regulation of apoptotic process

ECO:0000315:

P

Figure 5

complete
CACAO 4338

HUMAN:ULA1

involved_in

GO:0033314: mitotic DNA replication checkpoint

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ULA1

involved_in

GO:0043523: regulation of neuron apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ULA1

involved_in

GO:0042981: regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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