A CBP binding transcriptional repressor produced by the PS1/∈-cleavage of N-cadherin is inhibited by PS1FAD mutations
A CBP binding transcriptional repressor produced by the PS1/∈-cleavage of N-cadherin is inhibited by PS1FAD mutations
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DOI：
10.1016/j.cell.2003.08.008
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发表时间：
2003-09-05
期刊：
影响因子：
64.5
通讯作者：
Robakis, NK
中科院分区：
文献类型：
--
作者：
Marambaud, P;Wen, PH;Robakis, NK
早老素1（PS1）是一种与阿尔茨海默病（AD）有关的蛋白质，与N-钙粘蛋白形成复合物，N-钙粘蛋白是一种具有重要神经元和突触功能的跨膜蛋白。在这里，我们表明，PS1依赖的T-分泌酶蛋白酶活性促进ε-样切割的N-钙粘蛋白，产生其胞内结构域肽，N-Cad/CTF 2。NMDA受体激动剂刺激N-Cad/CTF 2产生，表明该受体调节N-钙粘蛋白的ε-裂解。N-Cad/CTF 2结合转录因子CBP并促进其蛋白酶体降解，抑制CRE依赖性反式激活。因此，PS1依赖的ε-裂解产物N-Cad/CTF 2作为CBP/CREB介导的转录的有效阻遏物发挥作用。重要的是，与家族性AD（FAD）相关的PS1突变和γ-分泌酶显性负突变抑制N-Cad/CTF 2的产生并上调CREB介导的转录，表明FAD突变通过抑制转录抑制因子N-Cad/CTF 2的产生而导致转录功能的获得。这些数据提出了FAD突变诱导的转录异常可能与FAD相关的痴呆症有因果关系的可能性。
Presenilin1 (PS1), a protein implicated in Alzheimer's disease (AD), forms complexes with N-cadherin, a transmembrane protein with important neuronal and synaptic functions. Here, we show that a PS1-dependent T-secretase protease activity promotes an epsilon-like cleavage of N-cadherin to produce its intracellular domain peptide, N-Cad/CTF2. NMDA receptor agonists stimulate N-Cad/CTF2 production suggesting that this receptor regulates the epsilon-cleavage of N-cadherin. N-Cad/ CTF2 binds the transcription factor CBP and promotes its proteasomal degradation, inhibiting CRE-dependent transactivation. Thus, the PS1-dependent epsilon-cleavage product N-Cad/CTF2 functions as a potent repressor of CBP/CREB-mediated transcription. Importantly, PS1 mutations associated with familial AD (FAD) and a gamma-secretase dominant-negative mutation inhibit N-Cad/CTF2 production and upregulate CREB-mediated transcription indicating that FAD mutations cause a gain of transcriptional function by inhibiting production of transcriptional repressor N-Cad/CTF2. These data raise the possibility that FAD mutation-induced transcriptional abnormalities maybe causally related to the dementia associated with FAD.