Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation
Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation
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DOI：
10.1073/pnas.0504600102
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发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Kahn, M
中科院分区：
文献类型：
--
作者：
Teo, JL;Ma, H;Kahn, M
Wnt/β-连环蛋白信号传导已被证明可以促进多种组织干细胞的自我更新，包括神经元干细胞和造血干细胞。然而，Wnt/β-连环蛋白途径的激活促进了神经元前体细胞的分化，而抑制该途径则阻止了神经元前体细胞的分化。目前还没有关于 Wnt/β-连环蛋白激活对神经元前体的不同影响的明确解释。 Presenilin-1 (PS-1) 是一种多胞体蛋白，由 6 至 8 个跨膜结构域组成。 PS-1 作为 γ 分泌酶复合物的一部分，是淀粉样前体蛋白 (APP) 和 Notch 的膜内蛋白水解所必需的。此外，通过与 β-连环蛋白相互作用，PS-1 与 Wnt/β-连环蛋白信号传导的调节相关。与家族性阿尔茨海默病相关的 PS-1 突变体 PS-1(L286V) 会导致 PC-12 细胞中 T 细胞因子 (TCF)/β-连环蛋白转录显着增加，从而阻止正常神经生长因子 (NGF) 诱导的神经元分化和神经突生长。最近描述的小分子拮抗剂 ICG-001 选择性抑制 TCF/β-连环蛋白/cAMP 反应元件结合蛋白 (CREB) 结合蛋白 (CBP) 介导的转录，但不抑制 TCF/β-连环蛋白/p300，从而纠正了神经元分化中的这些缺陷，突出了 Wnt/β-连环蛋白信号传导在此过程中的重要性。我们认为，TCF/β-连环蛋白/CBP 介导的转录增加，以及未能转换为 TCF/β-连环蛋白/p300 介导的转录，在减少神经元分化中发挥着重要作用。
Wnt/beta-catenin signaling has been shown to promote self-renewal in a variety of tissue stem cells, including neuronal stem cells and hematopoietic stem cells. However, activation of the Wnt/beta-catenin pathway promoted and inhibition of the pathway prevented differentiation of neuronal precursor cells. A clear explanation for the differential effects of Wnt/beta-catenin activation on neuronal precursors is not available at present. Presenilin-1 (PS-1) is a polytopic protein comprised of six to eight transmembrane domains. PS-1, as part of the gamma-secretase complex, is required for the intramembrane proteolysis of both amyloid precursor protein (APP) and Notch. Additionally, through interactions with beta-catenin, PS-1 is associated with modulation of Wnt/beta-catenin signaling. A familial Alzheimer's disease-associated PS-1 mutant, PS-1(L286V), causes a dramatic increase in T cell factor (TCF)/beta-catenin transcription in PC-12 cells, which prevents normal nerve growth factor (NGF)-induced neuronal differentiation and neurite outgrowth. Selective inhibition of TCF/beta-catenin/cAMP-response element-binding protein (CREB)-binding protein (CBP)-mediated transcription, but not TCF/beta-catenin/p300, with the recently described small molecule antagonist ICG-001 corrects these defects in neuronal differentiation, highlighting the importance of Wnt/beta-catenin signaling in this process. We propose that increased TCF/beta-catenin/CBP-mediated transcription, as well as a failure to switch to TCF/beta-catenin/p300-mediated transcription, play an important role in decreasing neuronal differentiation.