title: Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals.
abstract: 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.
authors.affiliation: Ganymed Pharmaceuticals AG, Freiligrathstr. Mainz, Germany. o.tureci@ganymed.ag
authors.forename: Ozlem
authors.initials: O
authors.lastname: Türeci
authors.forename: Michael
authors.initials: M
authors.lastname: Koslowski
authors.forename: Gerd
authors.initials: G
authors.lastname: Helftenbein
authors.forename: John
authors.initials: J
authors.lastname: Castle
authors.forename: Christoph
authors.initials: C
authors.lastname: Rohde
authors.forename: Karl
authors.initials: K
authors.lastname: Dhaene
authors.forename: Gerhard
authors.initials: G
authors.lastname: Seitz
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism; D057167:Claudins; D017124:Conserved Sequence; D004285:Dogs; D019143:Evolution, Molecular; D005753:Gastric Mucosa / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D000882:Haplorhini; D008322:Mammals / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D009928:Organ Specificity; D010802:Phylogeny; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D011817:Rabbits; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D013270:Stomach / Q000166:cytology; D014018:Tissue Distribution
chemical_list: C486683:CLDN18 protein, human; D057167:Claudins; C438899:Cldn18 protein, mouse; D008565:Membrane Proteins; D020033:Protein Isoforms; D050882:CREB-Binding Protein