The γ/ε-secretase-derived APP intracellular domain fragments regulate p53
The γ/ε-secretase-derived APP intracellular domain fragments regulate p53
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DOI：
10.2174/156720507781788945
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发表时间：
2007-09-01
影响因子：
2.1
通讯作者：
da Costal, Cristine Alves
中科院分区：
文献类型：
--
作者：
Checler, Frederic;Sunyach, Claire;da Costal, Cristine Alves
淀粉样β肽（AP）在阿尔茨海默病中起核心作用，它是由β - 淀粉样前体蛋白（βAPP）经早老素依赖和早老素非依赖的γ - 分泌酶切割产生的。我们报道早老素（PS1和PS2）也调节与p53相关的细胞死亡。因此，我们确定PS缺乏、无催化活性的PS突变体、γ - 分泌酶抑制剂以及βAPP或APLP2的缺失会降低p53的表达和活性，并降低其启动子的反式激活和mRNA水平。在βAPP缺陷小鼠的大脑中，或者在通过双条件敲除使两种PS均失活的大脑中，p53的表达也降低。AICD - C59和AICD - C50分别是PAPP经γ - 分泌酶和ε - 分泌酶切割产生的C末端片段，它们触发caspase - 3的激活、p53依赖的细胞死亡，并增加p53的活性和mRNA。最后，表达携带家族性阿尔茨海默病（FAD）突变的PS1的HEK293细胞或受FAD影响的大脑都显示出p53活性和p53表达增强。我们的研究表明，AICDs在体外和体内的转录水平上控制p53，并揭示了早老素一种尚不为人知的功能。
Amyloid beta-peptide (AP), which plays a central role in Alzheimer Disease, is generated by presenilin-dependent and presenilin-independent gamma-secretase cleavages of beta-amyloid precursor protein (beta APP). We report that the presenilins (PSI and PS2) also regulate p53-associated cell death Thus, we established that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors and beta APP or APLP2 depletion reduced the expression and activity of p53, and lowered the transactivation of its promoter and mRNA levels. p53 expression was also reduced in the brains or beta APP-deficient mice or in brains where both PS had been invalidated by double conditional knock out. AICDC59 and AICDC50, the gamma- and epsilon-secretase-derived C-terminal fragments of PAPP, respectively, trigger the activation of caspase-3, p53-dependent cell death, and increase p53 activity and mRNA. Finally, HEK293 cells expressing PSI harboring familial AD (FAD) mutations or FAD-affected brains, all display enhanced p53 activity and p53 expression. Our studies demonstrate that AICDs control p53 at a transcriptional level, in vitro and in vivo and unravel a still unknown function for presenilins.