Disease relevance of CLDN4

• Crucial roles of Sp1 and epigenetic modifications in the regulation of the CLDN4 promoter in ovarian cancer cells [1].
• CLDN4 appears to be over-expressed in ovarian and pancreatic carcinomas, and this raises the possibility that a unique, potentially non-toxic cancer cell target may be developed through the design of enterotoxin analogues [2].
• The loss of CLDN4 expression in areas of apocrine metaplasia and in the majority of grade 1 invasive carcinomas also suggests a particular role for this protein in mammary glandular cell differentiation and carcinogenesis [3].
• Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas [4].
• Claudin 4 was significantly increased in both borderline-type and ovarian adenocarcinomas compared to benign tumours, whereas no changes were found for claudin 1 or 5 [5].

Psychiatry related information on CLDN4

• Psychometric properties of the Chinese version of the Psycho-educational Profile-Revised (CPEP-R) [6].
• Regarding the concurrent validity of the CPEP-R, the developmental score and developmental age assessed by the CPEP-R were significantly correlated with the Merrill-Palmer Scale of Mental Tests and the Hong Kong Based Adaptive Behavior Scale [6].
• The Chinese PEP-R (CPEP-R) was administered to 63 preschool children with symptoms of autistic disorder recruited from special child-care centers in Hong Kong. Results showed that the scales of the CPEP-R were internally consistent, reliable across raters and temporally stable [6].

High impact information on CLDN4

• 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].
• A decrease in conductance correlated directly with the kinetics of claudin-4 induction [7].
• Epithelial resistance was diminished from 44 +/- 3 to 29 +/- 2 Omega x cm(2), and this was accompanied by a decrease in occludin and claudin-4 expression [8].
• Using expression profiling, we previously found claudin-4 to be overexpressed in pancreatic cancer [9].
• RESULTS: Expression analyses showed that claudin-4 was overexpressed in most pancreatic cancer tissues and cell lines and several other gastrointestinal tumors [9].

Chemical compound and disease context of CLDN4

• The expression of E-cadherin, claudin 4, and ZO-1 was analyzed immuno-histochemically using formalin-fixed, paraffin-embedded tissues obtained from 49 patients who underwent radical resection for advanced gastric cancer [10].
• Statistical analyses showed that the beta8 integrin subunit, claudin-4, and S100A1 provided the best distinction between ovarian carcinoma and normal ovary tissues, and may serve as the best candidate tumor markers among the seven genes studied [11].

Biological context of CLDN4

• However, because of the ubiquitous expression of Sp1, these sites, although necessary, are not sufficient to explain the patterns of gene expression of CLDN4 in various ovarian tissues [1].
• We show that the CLDN4 promoter is further controlled by epigenetic modifications of the Sp1-containing critical promoter region [1].
• In ovarian cancer cell lines, claudin-3 and claudin-4 expression was not associated with functional TJs as measured by transepithelial electrical resistance [4].
• Concerning relation to Federation for International Gynaecology and Obstetrics (FIGO) grade, claudin 3, but not claudin 4, was significantly increased in moderately, poorly and undifferentiated adenocarcinomas compared to well-differentiated and borderline-type tumours [5].
• A single nucleotide polymorphism (SNP) present in CPETR1 has been identified and was used to determine parental origin of the deleted allele in five informative families [12].

Anatomical context of CLDN4

• CONCLUSIONS: These results show that CLDN3 and CLDN4 are frequently up-regulated in ovarian tumors and cell lines and may represent novel markers for this disease [4].
• However, CLDN4 was highly positive in normal epithelial cells and was decreased or absent in 17 out of 21 ductal carcinoma grade 1, in special types of breast carcinoma (mucinous, papillary, tubular) and in areas of apocrine metaplasia [3].
• The observations of lack of claudin 4 and low expression of claudin 3 in OSE strengthen our current knowledge about the biological nature of these cells as an undeveloped epithelium [5].
• Northern blot analysis of CPETR1 demonstrates tissue specificity, with expression in kidney, lung, thyroid, and gastrointestinal tissues [12].
• Human and mouse cDNAs showing homology to the Clostridium perfringens enterotoxin (CPE) receptor gene (CPE-R) from Vero cells (DDBJ/EMBL/GenBankTM accession no. D88492) (Katahira, J., Inoue, N., Horiguchi, Y., Matsuda, M., and Sugimoto, N. (1997) J. Cell Biol. 136, 1239-1247) were cloned [13].

Associations of CLDN4 with chemical compounds

• They were classified into two groups, the Vero cell CPE receptor homologues and rat androgen withdrawal apoptosis protein (RVP1; accession no. M74067) homologues, based on the similarities of primary amino acid sequences [13].
• 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 [14].
• Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells [15].
• In addition to the decline in the barrier properties of the monolayers, extraction of cell cholesterol produced an increase in the Triton X-100 solubility of claudin 3, claudin 4 and occludin, and the loss of all three proteins from the plasma membrane (tight junctions) [16].
• Induction of claudin-4 by indomethacin was confirmed at both mRNA and protein levels [17].

Regulatory relationships of CLDN4

• WNK1 expression also induced phosphorylation of endogenous claudin-4 in MDCKII cells, as well as over-expressed claudin-4 [15].

Other interactions of CLDN4

• We also investigated whether high expression of claudin-3 and claudin-4 was associated with TJ function in ovarian cancer cells [4].
• These cancers may represent ideal candidates for a novel therapy being developed based on CPE, a toxin that specifically binds claudin-3 and claudin-4 [18].
• Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity [19].
• There was also a massive increase in expression of claudin 4 and 5 proteins which was due to inhibition of proteasomal degradation of claudin 4 and consequential stabilisation of the claudin 5 heterodimerisation partner [20].
• We have unexpectedly found that, in normal placentae, the multinucleated syncytiotrophoblast layer displays claudin 4 at the basal surface of the plasma membrane, and claudin 16 along the apical and basolateral surfaces [21].

Analytical, diagnostic and therapeutic context of CLDN4

• The in vivo effect of CPE was studied in claudin-4-expressing nude mouse xenografts of the Panc-1 cell line [9].
• Claudin-4 localization was characterized by light and electron microscopy, and pulmonary colonization was analyzed in vivo after injection of claudin-4 overexpressing cells into the tail vein of nude mice [22].
• Sucrose velocity centrifugation and laser light scattering are also used to investigate the oligomeric state of claudin-4 [23].
• Western blot analysis and RT-PCR also showed decreased claudin 4 expression in diffuse type tumors and poorly-differentiated adenocarcinoma [10].
• To explore the roles of claudin-4 in the two histologically distinct types of gastric cancer, we selected 45 IGC and 48 DGC cases and then analyzed the expression of the protein using immunohistochemistry [24].

References