6533b82efe1ef96bd1293260
RESEARCH PRODUCT
Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals
Gerhard SeitzJohn C. CastleMichael KoslowskiÖZlem TüreciKarl DhaeneChristoph RohdeGerd HelftenbeinUgur Sahinsubject
Gene isoformmiceMolecular Sequence DataGene Expressionmolecular structureMammals/geneticsBiologyphylogenyRATSConserved sequenceEvolution MolecularDogsProtein Isoforms/geneticsSequence Homology Nucleic AcidGene expressionGeneticsProtein IsoformsAnimalsTissue DistributionAmino Acid SequenceMembrane Proteins/geneticsBinding sitePromoter Regions GeneticClaudinGeneTranscription factorConserved SequenceGastric Mucosa/metabolismMammalsRegulation of gene expressionGeneticsBinding SitesBase SequenceStomachStomach/cytologyMembrane ProteinsCREB-Binding Protein/metabolismHaplorhiniGeneral MedicineCREB-Binding ProteinGene Expression RegulationGastric MucosaOrgan SpecificityMultigene FamilyClaudinsRabbitsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-08-01 | Gene |