The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons
The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons
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DOI：
10.1074/jbc.275.12.8929
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发表时间：
2000-03-24
影响因子：
4.8
通讯作者：
Neve, RL
中科院分区：
文献类型：
--
作者：
Chen, YZ;McPhie, DL;Neve, RL
APP-BP1与淀粉样前体蛋白(APP)的羧基末端结构域结合。最近的工作表明，APP-BP1参与了一种新的泛素化相关途径，涉及泛素样分子NEDD8。我们在这里显示，在哺乳动物细胞中，APP-BP1与其在NEDD8激活途径中的假定伙伴hUba3相互作用，并且hUba3的APP-BP1结合位点在氨基酸443-479范围内。我们还提供了证据表明，人APP-BP1分子可以挽救中国仓鼠细胞中的ts41突变。此前已有研究表明，这种突变会导致细胞出现连续的S期。没有干预G(2)、M和G(1)的周期，表明该基因的产物负向调节进入S期，正向调节进入有丝分裂。我们发现，APP-BP1在TS41细胞中的表达驱动细胞周期通过S-M检查点，并且这一功能同时需要hUba3和hUbc12。APP-BP1在原代神经元中的过表达可通过相同的途径引起细胞凋亡。一种特定的caspase-6抑制剂可以阻断这种细胞凋亡。这些发现是在阿尔茨海默病中观察到的细胞周期异常的背景下讨论的。
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.