Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals

Türeci, Özlem; Koslowski, Michael; Helftenbein, Gerd; Castle, John C.; Rohde, Christoph; Dhaene, Karl; Seitz, Gerhard; Şahin, Uğur

doi:10.1016/j.gene.2011.04.007

Cited by 68 publications

(58 citation statements)

References 28 publications

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“…For example, the Sp1 transcription factor is crucial for claudin-3 and claudin-4 promoter activity, and the epigenetic status, including DNA methylation and histone H3 acetylation, in the critical region containing the Sp1 binding site also plays an important role in regulating of claudin-3 and claudin-4 expression in ovarian cancer cells [71]. DNA hypomethylation and the transcription factor CREB are related to the transcriptional upregulation of claudin-18 splice variant 2 [75]. Recent studies have further demonstrated an epigenetic link between the activity of the EZH2 methyltransferase at the claudin-23 locus and the expression of claudin-23 in CRC tissue [76].…”

Section: Epigenetic and Mirna Regulation Of Claudin Expressionmentioning

confidence: 99%

Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact

Singh

Dhawan

2015

Seminars in Cell & Developmental Biology

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Section: Epigenetic and Mirna Regulation Of Claudin Expressionmentioning

confidence: 99%

Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact

Singh

Dhawan

2015

Seminars in Cell & Developmental Biology

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“…Cldn18 has 2 promoters, each with a unique exon 1 spliced to common exons 2 through 5. Alternative promoter usage leads to production of lung-and stomach-specific isoforms (22). Deletion of the stomach-specific Cldn18.2 isoform in mice leads to loss of TJ strands and increased paracellular H + leakage in the stomach, resulting in atrophic gastritis and metaplasia but without evidence of tumor formation (23).…”

Section: Introductionmentioning

confidence: 99%

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou¹,

Flodby²,

Luo³

et al. 2018

Journal of Clinical Investigation

125

116

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Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18 -/-AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18 -/-mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

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“…High expression of claudin 18 (Cldn18) has been described in lung and stomach epithelium (10,11), with lung-specific (C18.1) and stomach-specific (C18.2) isoforms of claudin 18 regulated by alternative promoter usage. Deletion of C18.2 in knockout (KO) mice was reported to result in the loss of TJ strands and increased paracellular H 1 leak in the stomach (12,13).…”

mentioning

confidence: 99%

Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

Flodby

Luo

et al. 2014

Am J Respir Cell Mol Biol

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Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJs) that regulate paracellular permeability to ions and solutes. Claudin 18, a member of the large claudin family, is highly expressed in lung alveolar epithelium. To elucidate the role of claudin 18 in alveolar epithelial barrier function, we generated claudin 18 knockout (C18 KO) mice. C18 KO mice exhibited increased solute permeability and alveolar fluid clearance (AFC) compared with wild-type control mice. Increased AFC in C18 KO mice was associated with increased b-adrenergic receptor signaling together with activation of cystic fibrosis transmembrane conductance regulator, higher epithelial sodium channel, and Na-K-ATPase (Na pump) activity and increased Na-K-ATPase b1 subunit expression. Consistent with in vivo findings, C18 KO alveolar epithelial cell (AEC) monolayers exhibited lower transepithelial electrical resistance and increased solute and ion permeability with unchanged ion selectivity. Claudin 3 and claudin 4 expression was markedly increased in C18 KO mice, whereas claudin 5 expression was unchanged and occludin significantly decreased. Microarray analysis revealed changes in cytoskeletonassociated gene expression in C18 KO mice, consistent with observed F-actin cytoskeletal rearrangement in AEC monolayers. These findings demonstrate a crucial nonredundant role for claudin 18 in the regulation of alveolar epithelial TJ composition and permeability properties. Increased AFC in C18 KO mice identifies a role for claudin 18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties that may, at least in part, compensate for increased permeability.

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Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals

Cited by 68 publications

References 28 publications

Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact

Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

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