ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis
ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis
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DOI：
10.1046/j.1471-4159.2003.01727.x
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发表时间：
2003-05-01
影响因子：
4.7
通讯作者：
Neve, RL
中科院分区：
文献类型：
--
作者：
Chen, YZ;Liu, WY;Neve, RL
APP- bp1首先被发现是一种与淀粉样蛋白前体蛋白（APP）的羧基(C)端相互作用的蛋白质，是泛素样蛋白NEDD8的二分激活酶的一半。我们在这里报道，APP-BP1还通过功能性主要n端结构域ASPP2特异性地与未转染细胞中的p53 ASPP2的p蛋白相互作用（332-483）。ASPP2抑制APP-BP1挽救ts41细胞周期突变的能力，抑制APP-BP1诱导的原代神经元凋亡。ASPP2降低NEDD8结合Cullin-1的能力，抑制APP-BP1依赖的ts41细胞增殖，阻断APP-BP1导致细胞凋亡和神经元DNA合成的能力。我们还发现，ASPP2激活核因子- kappab （NF-kappaB）转录活性，这似乎被类化化途径抑制，因为显性负NEDD8激活酶会导致NF-kappaB活性增强。我们的数据首次提供了体内证据，证明ASPP2通过与APP- bp1的特异性相互作用，是类化化通路的负调节因子，并提示APP- bp1与APP相互作用的功能障碍可能是阿尔茨海默病的一个原因。
APP-BP1, first identified as a protein that interacts with the carboxyl (C) terminus of the amyloid precursor protein (APP), is one-half of the bipartite activating enzyme for the ubiquitin-like protein NEDD8. We report here that APP-BP1 also specifically interacts with a poptosis s timulating p rotein of p 53 ASPP2 in non-transfected cells through the functional predominant N-terminal domain ASPP2(332-483). ASPP2 inhibits the ability of APP-BP1 to rescue the ts41 cell cycle mutation and inhibits APP-BP1 induced apoptosis in primary neurons. ASPP2 reduces the ability of NEDD8 to conjugate to Cullin-1, inhibits APP-BP1-dependent ts41 cell proliferation, and blocks the ability of APP-BP1 to cause apoptosis and to cause DNA synthesis in neurons. We also show that ASPP2 activates nuclear factor-kappaB (NF-kappaB) transcriptional activity, which seems to be inhibited by the neddylation pathway since the dominant negative NEDD8 activating enzyme causes enhanced NF-kappaB activity. Our data provide the first in vivo evidence that ASPP2 is a negative regulator of the neddylation pathway through specific interaction with APP-BP1 and suggest that dysfunction of the APP-BP1 interaction with APP may be one cause of Alzheimer's disease.