Department of Pharmacology and Neuroscience, Institute for Healthy Aging, UNT Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107,
Department of Pharmacology and Neuroscience, UNT Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107.
Front Biosci (Landmark Ed). 2020 Mar 1;25(7):1297-1304. doi: 10.2741/4856.
Presenilin-1 (PS1) is the catalytic subunit of gamma-secretase. PS1 cleaves beta-amyloid precursor protein (APP) to produce Abeta peptide and Notch 1 receptor to release Notch intracellular domain (NICD) in the cytoplasm. We have previously shown that rapamycin inhibits p-mTOR to repress PS1 transcription and Notch 1-signaling. But the exact mechanism by which rapamycin inhibits PS1 transcription is not known. We have also published that inhibition of basal activity of c-jun-NH2-terminal kinase (JNK) with JNK-specific inhibitor SP600125 represses PS1 transcription by reducing p-JNK and via p53 dependent mechanism. We now report that rapamycin inhibits the phosphorylation of both mTOR (p-mTOR) and JNK (p-JNK). It appears that rapamycin represses PS1 transcription by inhibiting the expression of p-JNK in SK-N-SH cells under non-stressed condition. Consequently, one of the mechanisms of inhibition of PS1 transcription by rapamycin is similar to the mechanism of repression of PS1 transcription by JNK-specific inhibitor SP600125. We also report that JNK-inhibitor SP6000125 decreases both p-JNK and p-mTOR protein levels. These results suggest that JNK and mTOR may potentially activate each other by mutual phosphorylation.
早老素 1（PS1）是γ-分泌酶的催化亚基。PS1 切割β-淀粉样前体蛋白（APP）产生 Abeta 肽和 Notch1 受体，在细胞质中释放 Notch 细胞内结构域（NICD）。我们之前已经表明雷帕霉素通过抑制 p-mTOR 来抑制 PS1 转录和 Notch1 信号。但是，雷帕霉素抑制 PS1 转录的确切机制尚不清楚。我们还发表了抑制基础活性的 c-jun-NH2-末端激酶（JNK）用 JNK 特异性抑制剂 SP600125 通过减少 p-JNK 和通过 p53 依赖性机制抑制 PS1 转录。我们现在报告雷帕霉素抑制 mTOR（p-mTOR）和 JNK（p-JNK）的磷酸化。雷帕霉素似乎通过在非应激条件下抑制 SK-N-SH 细胞中 p-JNK 的表达来抑制 PS1 转录。因此，雷帕霉素抑制 PS1 转录的机制之一与 JNK 特异性抑制剂 SP600125 抑制 PS1 转录的机制相似。我们还报告 JNK 抑制剂 SP6000125 降低了 p-JNK 和 p-mTOR 蛋白水平。这些结果表明 JNK 和 mTOR 可能通过相互磷酸化潜在地激活彼此。
