Hashimoto Yuichi, Takeshita Yuji, Naito Mikihiko, Uchino Hiroyuki, Matsuoka Masaaki
Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
Mol Cell Biochem. 2014 Dec;397(1-2):147-55. doi: 10.1007/s11010-014-2182-4. Epub 2014 Aug 20.
Humanin, a short bioactive peptide, inhibits a variety of cell deaths. Humanin-mediated inhibition of neuronal cell death, caused by an Alzheimer's disease (AD)-linked mutant gene occurs via binding of Humanin to its heterotrimeric Humanin receptor (htHNR), which results in the activation of the Janus-associated kinases (JAKs) and signal transducer and activator and transcription 3 (STAT3) signaling pathway. A previous study demonstrated that the Humanin-induced activation of the htHNR/JAK2/STAT3 signaling pathway leads to increased expression of SH3 domain-binding protein 5 (SH3BP5), which is an essential effector of Humanin's anti-cell death activity in some cultured neuronal cells. However, it remains unknown whether SH3BP5 is the sole effector of the Humanin signaling pathway via htHNR/JAKs/STAT3. Here we show that the Humanin signaling pathway via htHNR/JAKs/STAT3 increased the expression levels of mRNA and protein of Apollon/Bruce, an unusual member of the inhibitors of apoptosis proteins, and that overexpression of Apollon/Bruce inhibits neuronal death, caused by a London-type familial AD-linked mutant (V642I) of amyloid β precursor protein. Overall, the results indicate that expression of Apollon/Bruce is upregulated by Humanin, and Apollon/Bruce could be an effector of Humanin in a context-dependent manner.
人胰岛素（Humanin）是一种短小的生物活性肽，可抑制多种细胞死亡。人胰岛素介导的对由阿尔茨海默病（AD）相关突变基因引起的神经元细胞死亡的抑制作用，是通过人胰岛素与其异源三聚体人胰岛素受体（htHNR）结合而发生的，这导致Janus相关激酶（JAKs）以及信号转导和转录激活因子3（STAT3）信号通路的激活。先前的一项研究表明，人胰岛素诱导的htHNR/JAK2/STAT3信号通路的激活会导致SH3结构域结合蛋白5（SH3BP5）表达增加，在一些培养的神经元细胞中，SH3BP5是人胰岛素抗细胞死亡活性的关键效应因子。然而，尚不清楚SH3BP5是否是人胰岛素通过htHNR/JAKs/STAT3信号通路的唯一效应因子。在此我们表明，通过htHNR/JAKs/STAT3的人胰岛素信号通路增加了凋亡抑制蛋白中一个特殊成员Apollon/Bruce的mRNA和蛋白质表达水平，并且Apollon/Bruce的过表达抑制了由淀粉样β前体蛋白的伦敦型家族性AD相关突变体（V642I）引起的神经元死亡。总体而言，结果表明Apollon/Bruce的表达受人胰岛素上调，并且Apollon/Bruce可能在依赖于背景的情况下是人胰岛素的效应因子。
