Disease relevance of CLDN1

• In the sporadic tumors and hereditary breast cancer patients, we have found no evidence to support the involvement of aberrant CLDN1 in breast tumorigenesis [1].
• CLDN1 may support tumor suppressive functions in tissues such as the brain, where dramatic loss of expression has been demonstrated in glioblastoma multiforme [2].
• We documented increased expression of CLDN1 in all 16 primary colorectal cancers we examined, compared with adjacent noncancerous mucosae [3].
• CONCLUSIONS: The significant loss of CLDN1 protein in breast cancer cells suggests that CLDN1 may play a role in invasion and metastasis [4].
• CLDN1 was present in the membrane of normal duct cells and in some of the cell membranes from ductal carcinoma in situ, and was frequently observed in eight out of nine areas of apocrine metaplasia, whereas invasive tumours were negative for CLDN1 or it was present in a scattered distribution among such tumour cells (in 36/39 malignant tumours) [4].

High impact information on CLDN1

• The claudin family of genes is known to express protein components of tight junctions in other tissues [5].
• Genetic manipulations of claudin-1 expression in colon cancer cell lines induced changes in cellular phenotype, with structural and functional changes in markers of epithelial-mesenchymal transition [6].
• Here, we report an increased expression of claudin-1 in human primary colon carcinoma and metastasis and in cell lines derived from primary and metastatic tumors [6].
• Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer [6].
• To test whether members of the claudin family of tight junction proteins influence paracellular ionic selectivity, we expressed human claudin-4 in cultured MDCK cells using an inducible promoter [7].

Biological context of CLDN1

• CLDN1 expression in HMECs, in contrast to low or undetectable levels of expression in a number of breast tumors and breast cancer cell lines, points to CLDN1 as a possible tumor-suppressor gene [1].
• Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands [8].
• Northern blotting showed that the tissue distribution pattern varied significantly, depending on claudin species [8].
• Claudin expression also increased cell survival in HOSE cells but did not significantly affect cell proliferation [9].
• Amino acid substitutions or deletions in ectodomain of claudin-1 abolished stimulatory effect [10].

Anatomical context of CLDN1

• Recently, a claudin-1 (CLDN1) cDNA has been isolated from human mammary epithelial cells (HMECs) [1].
• Likewise, in the breast cancer cell lines, no genetic alterations in the promoter or coding sequences have been identified that would explain the loss of CLDN1 expression [1].
• Two related integral membrane proteins, claudin-1 and -2, recently were identified as novel components of tight junction (TJ) strands [8].
• Moderate claudin 1 and ZO-1 membranous staining were present, whereas only focal weak claudin 3 and 4 membranous staining was present in normal gastric epithelium [11].
• Consistent with this difference in barrier function, claudins expressed by HFL cells cultured in DCI medium were tightly localized to the plasma membrane; however, claudins expressed by HFL cells cultured in control medium accumulated in an intracellular compartment and showed discontinuities in claudin plasma membrane localization [12].

Associations of CLDN1 with chemical compounds

• The family of more than 20 claudin (CLDN) proteins comprises one of the major structural elements within the apical tight junction apparatus, a dynamic cellular nexus for maintenance of a luminal barrier, paracellular transport, and signal transduction [2].
• We examined claudin expression by human fetal lung (HFL) alveolar epithelial cells cultured in medium containing dexamethasone, 8-bromo-cAMP, and isobutylmethylxanthanine (DCI), which promotes alveolar epithelial cell differentiation to a type II phenotype [12].
• Immunocytochemistry and Western blotting showed that addition of azithromycin changed the locations of proteins in cell cultures and induced processing of the tight junction proteins claudin-1 and claudin-4, occludin, and junctional adhesion molecule-A [13].
• The distinct permeability properties observed in different epithelia and endothelia seemingly result from the restricted tissue expression, variability of the homopolymer and heteropolymer assembly, regulated transcription and translation, and the subcellular localization of claudin family proteins [14].
• theta Isoform of protein kinase C alters barrier function in intestinal epithelium through modulation of distinct claudin isotypes: a novel mechanism for regulation of permeability [15].

Co-localisations of CLDN1

• MT1-MMP was co-localized with claudin-1 not only at cell-cell borders, but also at other parts of the cells [10].

Regulatory relationships of CLDN1

• Claudin promotes activation of pro-matrix metalloproteinase-2 mediated by membrane-type matrix metalloproteinases [10].
• CLDN1 mRNA was downregulated by 12-fold in the sample (tumour) group as compared with the control group using GAPDH as the reference gene [4].
• Here we report evidence that the claudin-1 (CLDNI) gene is one of the genes regulated by beta-catenin [3].
• IL-17 induced formation of tight junctions correlated with up-regulation of claudin-1 and claudin-2 gene transcription [16].
• Accompanying these EGF-induced changes in claudin expression was a 3-fold increase in transepithelial resistance, a functional measure of TJs [17].

Other interactions of CLDN1

• These results suggest that claudin recruits all MT-MMPs and pro-MMP-2 on the cell surface to achieve elevated focal concentrations and, consequently, enhances activation of pro-MMP-2 [10].
• Furthermore, dendritic cells (DCs) of the medulla, with a major role for selection of thymocytes, expressed CLDN-1 and OCLN as well, implying that the interposition of DCs within the mTEC scaffold is also helped by TJs [18].
• Quantification performed determining the expression for TJ-molecules displayed diminished expression for CLDN-1 (p<0.01) and CLDN-5 (p<0.01) in patients with chronic venous insufficiency in comparison with healthy controls on mRNA as well as protein level [19].
• Our results indicate that occludin, claudin 1 and claudin 3 are involved in cell-to-cell contacts between keratinocytes in human epidermis, although their functional importance remains unknown [20].
• CLDN23 gene, frequently down-regulated in intestinal-type gastric cancer, is a novel member of CLAUDIN gene family [21].

Analytical, diagnostic and therapeutic context of CLDN1

• METHODS: Altogether, 56 sections from 52 surgically resected breast specimens were analyzed for CLDN1, CLDN3 and CLDN4 expression by immunohistochemistry. mRNA was also analyzed using real-time PCR in 17 of the 52 cases [4].
• Using real-time RT-PCR, we also surveyed a subset of 13 CLDN genes in 24 normal and 24 neoplastic tissues [22].
• We characterized the claudin expression in normal airways removed from human donors during lung transplantation and determined the contribution of each claudin to airway barrier function [23].
• The cellular immunofluorescence analysis of CLDN1 protein expression in transduced bulk cultures revealed a CLDN1-positive subfraction with a heterogeneous pattern of membrane and cytosolic immunostaining [24].
• In this report, we investigated the physiologic role of CLDN1 in CLDN1-transduced MDA-MB 361 breast tumor cells in adherent 2D and suspension 3D spheroid cell cultures [24].

References