Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
Gastroenterology. 2010 May;138(5):1823-35. doi: 10.1053/j.gastro.2010.01.050. Epub 2010 Feb 4.
BACKGROUND & AIMS: Gastrokines are stomach mucus cell-secreted proteins; 2 gastrokines are known, GKN1 and GKN2. Gastrokine expression is lost in gastric cancer, indicating a possible function in tumor suppression. We have identified a third gastrokine gene in mammals.
Gkn3 was characterized by studies of molecular structure, evolutionary conservation, and tissue expression as well as transcriptional/translational outcome in mouse genetic models of gastric pathology. The functional consequences of Gkn3 overexpression were evaluated in transfected cell lines.
Gkn3 encodes a secreted (approximately 19 kilodalton) protein that is co-expressed with trefoil factor (Tff)2 in the distal stomach and discriminates a Griffinia simplicifolia lectin (GS)-II-positive mucus neck cell (MNC) subpopulation in the proximal stomach. In humans, widespread homozygosity for a premature stop codon polymorphism, W59X, has likely rendered GKN3 non-functional. Population genetic analysis revealed an ancestral GKN3 read-through allele that predominates in Africans and indicates the rapid expansion of W59X among non-Africans during recent evolution. Mouse Gkn3 expression is strongly up-regulated in (Tff2-deficient) gastric atrophy, a pre-cancerous state that is typically associated with Helicobacter pylori and marks a non-proliferative, GS-II positive lineage with features of spasmolytic polypeptide-expressing metaplasia (SPEM). Gkn3 overexpression inhibits proliferation in gastric epithelial cell lines, independently of incubation with recombinant human TFF2 or apoptosis.
Gkn3 encodes a novel, functionally distinct gastrokine that is overexpressed and might restrain epithelial cell proliferation in gastric atrophy. Spread of the human GKN3 stop allele W59X might have been selected for among non-Africans because of its effects on pre-neoplastic outcomes in the stomach.
胃激肽是胃黏液细胞分泌的蛋白；已知有 2 种胃激肽，即 GKN1 和 GKN2。胃激肽在胃癌中表达缺失，提示其可能在肿瘤抑制中发挥作用。我们在哺乳动物中鉴定出第三种胃激肽基因。
通过对分子结构、进化保守性以及组织表达的研究，以及在胃病理的小鼠遗传模型中转录/翻译结果，对 Gkn3 进行了鉴定。在转染细胞系中评估了 Gkn3 过表达的功能后果。
Gkn3 编码一种分泌性（约 19 千道尔顿）蛋白，与 trefoil factor (Tff)2 在胃远端共同表达，并在胃近端区分 Griffinia simplicifolia 凝集素 (GS)-II 阳性黏液颈细胞 (MNC) 亚群。在人类中，广泛存在的提前终止密码子多态性 W59X 可能使 GKN3 失去功能。群体遗传学分析显示，一种原始的 GKN3 读通等位基因在非洲人中占优势，表明 W59X 在非非洲人中的快速扩张是在最近的进化过程中发生的。在（Tff2 缺陷）胃萎缩中，鼠 Gkn3 表达强烈上调，胃萎缩是一种癌前状态，通常与幽门螺杆菌相关，并标志着非增殖性、GS-II 阳性谱系，具有平滑肌多肽表达化生 (SPEM) 的特征。Gkn3 过表达可抑制胃上皮细胞系的增殖，而与重组人 TFF2 孵育或凋亡无关。
Gkn3 编码一种新型、功能独特的胃激肽，在胃萎缩中过度表达，并可能抑制上皮细胞增殖。人类 GKN3 终止等位基因 W59X 的传播可能在非非洲人中被选择，因为其对胃前肿瘤结果的影响。
