Disease relevance of Cldn1

• We have previously identified the human homologue of the murine Cldn1, CLDN1 (SEMP1) that is expressed in normal, mammary gland-derived epithelial cells but is absent in most human breast cancer cell lines [1].
• Among these, claudin-5 (also called transmembrane protein deleted in velo-cardio-facial syndrome [TMVCF]) was expressed ubiquitously, even in organs lacking epithelial tissues, suggesting the possible involvement of this claudin species in endothelial TJs [2].
• We investigated whether claudin-1, a component of tight junctions, regulated invasion activity in oral squamous cell carcinoma (OSC) cells [3].
• Differential expression of claudin family proteins in mouse ovarian serous papillary epithelial adenoma in aging FSH receptor-deficient mutants [4].
• The peptide toxin Clostridium perfringens enterotoxin (CPE) has been shown to bind to claudin-3 and -4, but not to claudin-1 or -2 [5].

High impact information on Cldn1

• Both cell lines maintained a luminal epithelial phenotype as evidenced by expression of the tight junction proteins, claudin-1 and occludin, and by generation of a high transepithelial electrical resistance on semipermeable filters [6].
• We found that claudin-19, a novel member of the claudin family (TJ adhesion molecules in epithelia), constituted these structures [7].
• These findings have indicated that, similar to epithelial cells, Schwann cells also bear claudin-based TJs, and they have also suggested that these TJs are not involved in the polarized morphogenesis but are involved in the electrophysiological "sealing" function of Schwann cells [7].
• These findings led to a molecular architectural model for TJs: small aggregates of JAM are tethered to claudin-based strands through ZO-1, and these JAM aggregates recruit PAR-3 to TJs [8].
• C-CPE bound to claudin-3 and -4 with high affinity, but not to claudin-1 or -2 [9].

Biological context of Cldn1

• Taken together, claudin-19 is a claudin isoform that is highly and specifically expressed in renal tubules with a putative role in TJ homeostasis in renal physiology [10].
• Mouse claudin-19 composes of 224 amino acids and shares 98.2% and 95% amino acid homology with rat and human, respectively; the most evolutionary-related claudins are claudin-1 and -7, which share approximately 75% DNA sequence homology with claudin-19 [10].
• The gene product exhibits an amino acid sequence similar to those of the claudin multigene family of proteins that constitute tight junction strands in epithelial cells [11].
• Using mouse L-fibroblast transfectants expressing various amounts of claudin-1, -2 or -3, we found that these claudins possess Ca(2+)-independent cell-adhesion activity [12].
• Thr203 of claudin-1, a putative phosphorylation site for MAP kinase, is required to promote the barrier function of tight junctions [13].

Anatomical context of Cldn1

• Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells [2].
• The influence of claudin-1 small interfering RNA (siRNA) on the invasion activity of the cell lines was also investigated [3].
• TM4SF10 is the vertebrate orthologue of Caenorhabditis elegans VAB-9, a tetraspan adherens junction protein in the PMP22/EMP/Claudin family of proteins [14].
• Expression of TM4SF10, a Claudin/EMP/PMP22 family cell junction protein, during mouse kidney development and podocyte differentiation [14].
• Here, we show that a fusion protein of GFP with claudin-1 can also form similar paired strands in L fibroblasts, allowing us to directly observe individual paired claudin strands in live cells in real time [15].

Associations of Cldn1 with chemical compounds

• Therefore, the distributions of claudin-1, -2, -3, -4, -8, -10, -11, and -16 in nephron segments were examined with immunofluorescence microscopy [16].
• Consistently, levels of both detergent-insoluble claudin-1 protein and its threonine-phosphorylation after Dox treatment were low in RLE:rtTA:CL1T203A cells compared to RLE:rtTA:CL1 cells [13].
• In glutaraldehyde-fixed samples, claudin-1-induced strands were largely associated with the protoplasmic (P) face as mostly continuous structures, whereas claudin-2-induced strands were discontinuous at the P face with complementary grooves at the extracellular (E) face which were occupied by chains of particles [17].
• Treatment with a GJIC blocker, 18 beta-glycyrrhetinic acid, resulted in decreases of occludin and claudin-1 at cell borders in the stable transfectants [18].
• Testosterone treatment significantly increased claudin-1 expression in immature Sertoli cells, suggesting the possible regulation of claudin-1 expression by androgen in mouse Sertoli cells [19].

Physical interactions of Cldn1

• Transfection experiments with various promoter constructs as well as electrophoretic mobility assays revealed that Snail binds directly to the E-boxes of the promoters of claudin/occludin genes, resulting in complete repression of their promoter activity [20].
• So far among these candidate proteins, dynein, claudin and silencer of death domains co-immunoprecipitated with the CSF-1R, suggesting association [21].

Co-localisations of Cldn1

• The myc-tagged claudin-1 precisely colocalized with both occludin and ZO-1 at cell-cell contact sites, indicating that exogenous claudin-1 was properly targeted to the TJs [22].

Other interactions of Cldn1

• Occludin and 18 distinct members of the claudin family are tetra-span transmembrane proteins that are localized in cell-specific tight junctions (TJs) [23].
• Their unique molecular composition, with claudin-11 accompanied by claudin-1 and claudin-2 points to a unique regulatory mechanism of the blood-CSF-barrier function [24].
• Characteristics of claudin expression in follicle-associated epithelium of Peyer's patches: preferential localization of claudin-4 at the apex of the dome region [25].
• We examined the expression and distribution of claudin-1 to claudin-18 (except for claudin-7, -13 and -17) in the inner ear by immunofluorescence microscopy [26].
• ZO-1 immunocytochemistry and claudin-1 immunofluorescence in mdx mice revealed a diffuse staining of microvessels as compared with the control ones, which displayed a banded staining pattern [27].

Analytical, diagnostic and therapeutic context of Cldn1

• However, confocal microscopy revealed a marked subjunctional localization of claudin-1 in C11 cells, indicating that claudin-1 is not functionally related to the low tight junctional resistance of C11 cells [28].
• As the first step in understanding the physiologic functions of claudins (tight junction integral membrane proteins) in nephrons, the expression of claudin-1 to -16 in mouse kidneys was examined by Northern blotting [16].
• Real-time RT-PCR studies revealed that Z310 cells possess mRNAs encoding ZO-1, -2, and -3, claudin-1, -2, -4, and -8, occludin, and connexin-32 [29].
• To verify the role of paracrine interactions between the Sertoli and Leydig cells in the structure and function of BTB in testis, the expression of claudin-1 and -11, and transepithelial electrical resistance (TER) of the mouse Sertoli cells were examined under the Leydig cell coculture [30].
• We recently identified by microarray analysis, members of this family, particularly claudin 1 (cldn1), as highly upregulated genes in the mouse mammary gland during early involution [31].

References