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Publication Record


Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/β-catenin signaling.
Ahmad R, Kumar B, Chen Z, Chen X, Müller D, Lele SM, Washington MK, Batra SK, Dhawan P, Singh AB
(2017) Oncogene 36: 6592-6604
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Cell Transformation, Neoplastic, Claudin-3, Colon, Colonic Neoplasms, Colorectal Neoplasms, Cytokine Receptor gp130, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, Intestinal Mucosa, Mice, Mice, Knockout, Permeability, STAT3 Transcription Factor, Up-Regulation, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added March 14, 2018
The hyperactivated Wnt/β-catenin signaling acts as a switch to induce epithelial to mesenchymal transition and promote colorectal cancer. However, due to its essential role in gut homeostasis, therapeutic targeting of this pathway has proven challenging. Additionally, IL-6/Stat-3 signaling, activated by microbial translocation through the dysregulated mucosal barrier in colon adenomas, facilitates the adenoma to adenocarcinomas transition. However, inter-dependence between these signaling pathways and key mucosal barrier components in regulating colon tumorigenesis and cancer progression remains unclear. In current study, we have discovered, using a comprehensive investigative regimen, a novel and tissue-specific role of claudin-3, a tight junction integral protein, in inhibiting colon cancer progression by serving as the common rheostat of Stat-3 and Wnt-signaling activation. Loss of claudin-3 also predicted poor patient survival. These findings however contrasted an upregulated claudin-3 expression in other cancer types and implicated role of the epigenetic regulation. Claudin-3-/- mice revealed dedifferentiated and leaky colonic epithelium, and developed invasive adenocarcinoma when subjected to colon cancer. Wnt-signaling hyperactivation, albeit in GSK-3β independent manner, differentiated colon cancer in claudin-3-/- mice versus WT-mice. Claudin-3 loss also upregulated the gp130/IL6/Stat3 signaling in colonic epithelium potentially assisted by infiltrating immune components. Genetic and pharmacological studies confirmed that claudin-3 loss induces Wnt/β-catenin activation, which is further exacerbated by Stat-3-activation and help promote colon cancer. Overall, these novel findings identify claudin-3 as a therapeutic target for inhibiting overactivation of Wnt-signaling to prevent CRC malignancy.
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21 MeSH Terms
Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.
Wu J, Peng D, Zhang Y, Lu Z, Voehler M, Sanders CR, Li J
(2015) Biochem Biophys Res Commun 459: 87-93
MeSH Terms: Amino Acid Motifs, Claudin-1, Claudin-2, Claudin-3, Claudin-5, Claudins, Humans, Nuclear Magnetic Resonance, Biomolecular, Peripheral Nerves, Protein Structure, Secondary, Zonula Occludens-2 Protein
Show Abstract · Added February 5, 2016
Our recent study has shown that cellular junctions in myelin and in the epi-/perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ₁ domain of zonula occludens (ZO₁ or ZO₂) and the C-termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ₁ domain of ZO₂ and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi-/perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ₁ of ZO₂. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ₁, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO₂. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves.
Published by Elsevier Inc.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepithelial resistance in Madin-Darby canine kidney cells.
Singh AB, Harris RC
(2004) J Biol Chem 279: 3543-52
MeSH Terms: Acetylcysteine, Adherens Junctions, Animals, Blotting, Northern, Bromodeoxyuridine, Cell Adhesion, Cell Differentiation, Cell Division, Cell Line, Claudin-1, Claudin-3, Claudin-4, Claudins, Cycloheximide, Detergents, Dogs, Epithelium, ErbB Receptors, Gene Expression Regulation, Hepatocyte Growth Factor, Immunoblotting, Kidney, Membrane Proteins, Microscopy, Fluorescence, Neoplasms, Octoxynol, Phenotype, Protein Synthesis Inhibitors, Signal Transduction, Tight Junctions, Time Factors
Show Abstract · Added August 19, 2013
Tight junctions (TJs) are the most apical cell-cell junctions, and claudins, the recently identified TJ proteins, are critical for maintaining cell-cell adhesion in epithelial cell sheets. Based on their in vivo distribution and the results of overexpression studies, certain claudins, including claudin-1 and -4, are postulated to increase, whereas other claudins, especially claudin-2, are postulated to decrease the overall transcellular resistance. The overall ratio among claudins expressed in a cell/tissue has been hypothesized to define the complexity of TJs. Disruption of the TJs contributes to various human diseases, and a correlation between reduction of TJ function and tumor dedifferentiation has been postulated. The epidermal growth factor (EGF) receptor (EGFR) is overexpressed in a wide spectrum of epithelial cancers, and its expression correlates with a more metastatic cancer phenotype. However, normal functioning of EGFR is essential for normal epithelial cell proliferation and differentiation. The role of EGFR-dependent signaling in the development and maintenance of epithelial TJ integrity has not been studied in detail. This study demonstrates that, in polarized Madin-Darby canine kidney II cells, EGF-induced EGFR activation significantly inhibited claudin-2 expression while simultaneously inducing cellular redistribution and increased expression of claudin-1, -3, and -4. Accompanying these EGF-induced changes in claudin expression was a 3-fold increase in transepithelial resistance, a functional measure of TJs. In contrast, there were no alterations in protein expression and/or intracellular localization of other TJ-related proteins (ZO-1 and occludin) or adherens junction-associated proteins (E-cadherin and beta-catenin), suggesting that EGF regulates TJ function through selective and differential regulation of claudins.
1 Communities
2 Members
0 Resources
31 MeSH Terms