Di Stadio Chiara Stella, Altieri Filomena, Minopoli Giuseppina, Miselli Giuseppina, Rippa Emilia, Arcari Paolo
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Biochimie. 2017 Apr;135:149-153. doi: 10.1016/j.biochi.2017.02.007. Epub 2017 Feb 16.
Gastrokine 1 (GKN1) is highly expressed in gastric tissue and is secreted into the stomach but is not expressed in gastric cancer. GKN1 belongs to the BRICHOS domain family and plays a major role in maintaining gastric mucosa integrity. We previously demonstrated that a recombinant human GKN1 protein was able to interact with the amyloid precursor protein (APP) and was endowed with an anti-amyloidogenic property because it inhibited polymerization of the Aβ(1-40) peptide released from APP upon its partial hydrolysis. Here, we report that GKN1 can act as a physiological suppressor of Aβ production in gastric cancer cells. GKN1 blocked the access of γ-secretase to APP, thereby facilitating the cleavage of APP by α- and β-secretases. GKN1 directly interacted with APP C-terminal fragments, C83 and C99. In addition, it did not affect γ-secretase activity in gastric cancer cells because it did not alter Notch1 processing. GKN1-mediated inhibition of APP processing might represent a new approach for the prevention and therapy of Alzheimer's disease (AD).
胃动素1（GKN1）在胃组织中高表达并分泌到胃内，但在胃癌中不表达。GKN1属于BRICHOS结构域家族，在维持胃黏膜完整性方面起主要作用。我们之前证明，重组人GKN1蛋白能够与淀粉样前体蛋白（APP）相互作用，并具有抗淀粉样生成特性，因为它抑制了APP部分水解后释放的Aβ（1-40）肽的聚合。在此，我们报告GKN1可作为胃癌细胞中Aβ产生的生理抑制剂。GKN1阻止γ-分泌酶接近APP，从而促进α-和β-分泌酶对APP的切割。GKN1直接与APP的C末端片段C83和C99相互作用。此外，它不影响胃癌细胞中的γ-分泌酶活性，因为它不改变Notch1的加工过程。GKN1介导的对APP加工的抑制可能代表了一种预防和治疗阿尔茨海默病（AD）的新方法。
