Role of 14-3-3γ in FE65-dependent Gene Transactivation Mediated by the Amyloid β-Protein Precursor Cytoplasmic Fragment*
Role of 14-3-3γ in FE65-dependent Gene Transactivation Mediated by the Amyloid β-Protein Precursor Cytoplasmic Fragment*
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DOI：
10.1074/jbc.m504278200
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发表时间：
2005-12
影响因子：
4.8
通讯作者：
Akio Sumioka;S. Nagaishi;T. Yoshida;A. Lin;M. Miura;Toshiharu Suzuki
中科院分区：
文献类型：
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作者：
Akio Sumioka;S. Nagaishi;T. Yoshida;A. Lin;M. Miura;Toshiharu Suzuki
淀粉样β蛋白前体细胞内结构域片段（AICD）是由淀粉样β蛋白前体通过连续切割产生的。AICD被认为激活FE 65依赖的基因表达，但分子机制仍在考虑中。我们发现，二聚体14-3-3γ同时结合AICD和FE 65，并且这种结合通过增强AICD与FE 65的缔合而促进FE 65依赖的基因反式激活。14-3-3γ与AICD的667 VTPEER 672基序结合，最有趣的是，该基序中AICD在Thr-668处的磷酸化抑制了与14-3-3γ的相互作用并阻断了基因的反式激活。14-3-3γ需要在WW结构域和FE 65的第一个磷酸酪氨酸相互作用结构域之间的序列与FE 65结合。该区域的缺失阻断了14-3-3γ与FE 65的结合，并抑制了AICD介导的FE 65依赖性基因的反式激活，尽管缺失突变体FE 65仍然能够结合Tip 60，Tip 60是一种与FE 65在细胞核中形成复合物的组蛋白乙酰转移酶。综上所述，这些数据表明，14-3-3γ通过形成含有AICD和FE 65的复合物促进FE 65依赖性基因反式激活，并且AICD的磷酸化通过14-3-3γ和/或FE 65从AICD的解离下调FE 65依赖性基因反式激活。我们的研究结果表明，AICD与FE 65和14-3-3γ的多重相互作用调节FE 65依赖的基因反式激活。
The amyloid β-protein precursor intracellular domain fragment (AICD) is generated from amyloid β-protein precursor by consecutive cleavages. AICD is thought to activate FE65-dependent gene expression, but the molecular mechanism remains under consideration. We found that dimeric 14-3-3γ bound both AICD and FE65 simultaneously, and this binding facilitated FE65-dependent gene transactivation by enhancing the association of AICD with FE65. 14-3-3γ bound to the 667VTPEER672 motif of AICD and, most interestingly, the phosphorylation of AICD at Thr-668 in this motif inhibited the interaction with 14-3-3γ and blocked gene transactivation. 14-3-3γ required a sequence between the WW domain and the first phosphotyrosine interaction domain of FE65 for association with FE65. Deletion of this region blocked 14-3-3γ binding to FE65 and suppressed AICD-mediated FE65-dependent gene transactivation, although the deletion mutant FE65 was still able to bind Tip60, a histone acetyltransferase that forms a complex with FE65 in the nucleus. Taken together, these data demonstrate that 14-3-3γ facilitates FE65-dependent gene transactivation by forming a complex containing AICD and FE65, and phosphorylation of AICD down-regulates FE65-dependent gene transactivation through the dissociation of 14-3-3γ and/or FE65 from AICD. Our findings suggest that multiple interactions of AICD with FE65 and 14-3-3γ modulate FE65-dependent gene transactivation.