Ganymed Pharmaceuticals AG, Freiligrathstr. Mainz, Germany.
Gene. 2011 Aug 1;481(2):83-92. doi: 10.1016/j.gene.2011.04.007. Epub 2011 May 4.
Claudin-18 isoform 2 (CLDN18.2) is one of the few members of the human claudin family of tight junction molecules with strict restriction to one cell lineage. The objective of the current study was to compare molecular structure and tissue distribution of this gastrocyte specific molecule in mammals. We show here that the CLDN18.2 protein sequence is highly conserved, in particular with regard to functionally relevant domains in mouse, rat, rabbit, dog, monkey and human and also in lizards. Moreover, promoter regions of orthologs are highly homologous, including the binding site of the transcription factor cyclic AMP-responsive element binding protein (CREB), which is known to regulate activation of human CLDN18.2. Employing RT-PCR and immunohistochemistry, we found that, analogous to the human gene, all orthologous CLDN18.2 transcripts and proteins are exclusively expressed in differentiated gastric cells. Gene structure, promoter elements and RNA expression pattern of the lung-tissue specific Claudin-18 isoform 1 (CLDN18.1) as well, are homologous across species. These findings exemplify phylogenetic conservation of lineage-specific members of a multigene family. Given that CLDN18.2 is a novel drug target candidate, our data is also relevant for drug development as it reveals all six investigated mammalian species as suitable models for testing safety of CLDN18.2 targeting regimen.
紧密连接分子 Claudin-18 同种型 2（CLDN18.2）是人类 Claudin 紧密连接分子家族中少数严格限制在一个细胞谱系中的成员之一。本研究的目的是比较这种胃细胞特异性分子在哺乳动物中的分子结构和组织分布。我们在这里表明，CLDN18.2 蛋白序列高度保守，特别是在小鼠、大鼠、兔、狗、猴子和人类以及蜥蜴中与功能相关的结构域高度保守。此外，同源物的启动子区域高度同源，包括转录因子环腺苷酸反应元件结合蛋白（CREB）的结合位点，已知该蛋白调节人 CLDN18.2 的激活。通过 RT-PCR 和免疫组织化学，我们发现与人类基因类似，所有同源的 CLDN18.2 转录本和蛋白仅在分化的胃细胞中表达。肺组织特异性 Claudin-18 同种型 1（CLDN18.1）的基因结构、启动子元件和 RNA 表达模式在物种间也是同源的。这些发现体现了多基因家族中谱系特异性成员的系统发育保守性。鉴于 CLDN18.2 是一个新的药物靶点候选物，我们的数据对于药物开发也很重要，因为它表明所有六种被研究的哺乳动物物种都适合作为测试 CLDN18.2 靶向方案安全性的模型。
