Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.
Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors.
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DOI：
10.3233/jad-2009-0990
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发表时间：
2009
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影响因子：
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通讯作者：
Linqing Ma;Y. Ohyagi;Katsue Miyoshi;N. Sakae;K. Motomura;T. Taniwaki;H. Furuya;K. Takeda;T. Tabira;J. Kira
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文献类型：
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作者：
Linqing Ma;Y. Ohyagi;Katsue Miyoshi;N. Sakae;K. Motomura;T. Taniwaki;H. Furuya;K. Takeda;T. Tabira;J. Kira
早老素1(PS1)基因突变是早发性家族性阿尔茨海默病的主要原因，已知的是增加淀粉样β42(Abeta42)的产生以及促进细胞凋亡。我们最近报道，细胞内Abeta42激活P53基因的表达，促进P53依赖的细胞凋亡。在这里，我们检测了野生型和I143T/G384A突变型PS1基因转染细胞中P53的mRNA和蛋白水平。尽管基础的P53基因水平没有改变，但突变型PS1转基因细胞的P53蛋白水平显著升高。用凋亡诱导剂处理后，突变型PS1转基因细胞的P53蛋白水平显著升高，但P53基因表达水平未见明显提高。用β分泌酶抑制剂和伽马分泌酶抑制剂处理后，淀粉样β蛋白前体(AbetaPP)和PS1双基因转染组细胞内Abeta水平下降，突变型PS1转染组细胞内P53蛋白表达上调。此外，我们还发现，与野生型PS1转基因细胞相比，突变型PS1转基因细胞的蛋白酶体活性降低。AbetaPP/PS1双基因转染组蛋白酶体活性进一步降低。综上所述，I143T/G384A突变型PS1基因上调的P53依赖性细胞凋亡可能至少部分与细胞内Abeta和蛋白酶体损伤有关。
Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-beta42 (Abeta42) production as well as to promote apoptosis. We have recently reported that intracellular Abeta42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a beta-secretase inhibitor and gamma-secretase inhibitor decreased the intracellular Abeta levels in amyloid-beta protein precursor (AbetaPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AbetaPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Abeta and proteasome impairment.