Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Guillemot, Laurent; Citi, Sandra

doi:10.1091/mbc.e06-02-0122

Cited by 100 publications

(149 citation statements)

References 28 publications

Supporting

Mentioning

138

Contrasting

Unclassified

Order By: Relevance

“…This protein is known to convert TJ from a tight to a leaky strand phenotype (20), and its expression is regulated by cingulin, another TJ cytoplasmic plaque protein that modulates proliferation in Madin-Darby canine kidney cells (27). The transcriptional regulation of CLDN2 by nuclear symplekin provides a potential explanation for the similarities of their expression pattern in human CRC, where claudin-2 also is overexpressed (23), and in healthy human and rodent colonic epithelia, where claudin-2 expression is restricted to the bottom section of the Lieberkühn crypts (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Büchert

Papin

Bonnans

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Symplekin is a ubiquitously expressed protein involved in cytoplasmic RNA polyadenylation and transcriptional regulation and is localized at tight junctions (TJs) in epithelial cells. Nuclear symplekin cooperates with the Y-box transcription factor zonula occludens 1-associated nucleic acid-binding protein (ZONAB) to increase the transcription of cell cycle-related genes and also inhibits differentiation of intestinal cells. We detected high levels of nuclear symplekin in 8 of 12 human colorectal cancer (CRC) samples. shRNAmediated reduction of symplekin expression was sufficient to decrease significantly the anchorage-independent growth and proliferation of HT-29 CRC cells as well as their tumorigenicity when injected into immunodeficient animals. Symplekin downregulation also was found to alter ion transport through TJs, to promote the localization of ZONAB in the membrane rather than the nucleus, and strongly to enhance cell polarization in a 3D matrix, leading to the formation of spheroids organized around a central lumen. Claudin-2 expression was reduced following symplekin down-regulation, an effect mimicked when ZONAB expression was down-regulated using selective siRNA. Virus-mediated restoration of claudin-2 expression was found to restore nuclear expression of ZONAB in HT29ΔSym cells and to rescue the phenotypic alterations induced by symplekin down-regulation of cell polarity, paracellular transport, ZONAB localization, cyclin D1 expression, proliferation, and anchorage-independent growth. Finally, siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization, similar to observations in symplekindepleted cells. Our results suggest that nuclear overexpression of symplekin promotes tumorigenesis in the human colon and that the regulation of claudin-2 expression is instrumental in this effect.polarity | transcription | tumorigenesis | colorectal | tight junctions

show abstract

Section: Discussionmentioning

confidence: 99%

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Büchert

Papin

Bonnans

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In addition, downregulation of some tight junction proteins is known to increase epithelial proliferation in invertebrate 39 and vertebrate model systems. [40][41][42] The disruption of the tight junction multiprotein complex may also affect the establishment and maintenance of the polarized phenotype. Although it remains unclear if and how the modified expression of any given specific tight junction protein is associated with cancer pathogenesis, our study suggests that it may be useful to understand cancer histogenesis.…”

Section: Discussionmentioning

confidence: 99%

Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

et al. 2007

Self Cite

View full text Add to dashboard Cite

We investigated the expression of tight junction proteins in human lung squamous cell carcinomas and adenocarcinomas by immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). We found a statistically significant correlation between diagnosis and positivity of tumors with either claudin (CLDN)-1 or CLDN-5. Squamous cell carcinomas and basal cells of bronchial epithelium were positive for CLDN-1 and negative for CLDN-5, whereas adenocarcinomas, normal cylindrical cells and pneumocytes were positive for CLDN-5 and negative for CLDN-1, suggesting different pathways in tumor development and progression. CLDN-4 and ZO-1 staining were detected in both types of tumors, whereas cingulin (CGN) was not detected in squamous cell carcinomas. Quantitative RT-PCR was used to evaluate changes in transcript levels for a large panel of tight junction proteins. In squamous cell carcinomas, we observed statistically significant decreases in the mRNA levels of JAM-1, occludin, CLDN-3, CLDN-4, CLDN-7, CGN, ZO-2 and ZO-3, and an increase in CLDN-1 mRNA. In adenocarcinomas, when transcript levels were compared with bronchial cells, we observed statistically significant decreases in the mRNA levels of CLDN-1, CLDN-3, CLDN-4, CLDN-7, ZO-2 and ZO-3. These results indicate that characterization of tight junction protein expression in human lung tumors can be an additional diagnostic tool and provide new insights on their histogenesis. Modern Pathology (2007) 20, 947-954;

show abstract

“…Among these, cingulin and paracingulin (also known as cingulin-like protein 1, CGNL1, or JACOP) (24 -27) play an important role in the regulation of RhoA and Rac1 activities (27)(28)(29)(30). For example, both cingulin and paracingulin recruit GEF-H1, a RhoA activator, to junctions, resulting in the down-regulation of RhoA activity in confluent monolayers (28,29,31). In addition, paracingulin promotes the activation of Rac1 during junction formation upon calcium switch, by recruiting the Rac1 activator Tiam1 to junctions (29).…”

Section: Tight Junctions (Tj)mentioning

confidence: 99%

“…In summary, in MDCK cells PLEKHA7 promotes the expression of paracingulin and its recruitment to AJ, and neither cingulin nor paracingulin affects the junctional recruitment of TJ and AJ proteins (see also Refs. 29,31,32).…”

Section: Plekha7 But Not P120ctn Is Required To Maintain the Expressimentioning

confidence: 99%

A Role for ZO-1 and PLEKHA7 in Recruiting Paracingulin to Tight and Adherens Junctions of Epithelial Cells

Pulimeno

Paschoud

Citi

2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Paracingulin is a 160-kDa protein localized in the cytoplasmic region of epithelial tight and adherens junctions, where it regulates RhoA and Rac1 activities by interacting with guanine nucleotide exchange factors. Here, we investigate the molecular mechanisms that control the recruitment of paracingulin to cell-cell junctions. We show that paracingulin forms a complex with the tight junction protein ZO-1, and the globular head domain of paracingulin interacts directly with ZO-1 through an N-terminal region containing a conserved ZIM (ZO-1-Interaction-Motif) sequence. Recruitment of paracingulin to cadherinbased cell-cell junctions in Rat1 fibroblasts requires the ZIMcontaining region, whereas in epithelial cells removal of this region decreases the junctional localization of paracingulin at tight junctions but not at adherens junctions. Depletion of ZO-1, but not ZO-2, reduces paracingulin accumulation at tight junctions. A yeast two-hybrid screen identifies both ZO-1 and the adherens junction protein PLEKHA7 as paracingulin-binding proteins. Paracingulin forms a complex with PLEKHA7 and its interacting partner p120ctn, and the globular head domain of paracingulin interacts directly with a central region of PLEKHA7. Depletion of PLEKHA7 from Madin-Darby canine kidney cells results in the loss of junctional localization of paracingulin and a decrease in its expression. In summary, we characterize ZO-1 and PLEKHA7 as paracingulin-interacting proteins that are involved in its recruitment to epithelial tight and adherens junctions, respectively. Tight junctions (TJ)2 and adherens junctions (AJ) are key elements of the apical junctional complex of vertebrate epithelial cells and are of fundamental importance in the morphogenesis and homeostasis of epithelial tissues. TJ and AJ carry out several functions: canonical roles in cell-cell adhesion and tissue sorting (AJ), cell polarization and permeability barrier functions (TJ), and signaling functions through pathways that control the organization of the cytoskeleton and the activity of transcription factors (for review, see Refs.

show abstract

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Cited by 100 publications

References 28 publications

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

A Role for ZO-1 and PLEKHA7 in Recruiting Paracingulin to Tight and Adherens Junctions of Epithelial Cells

Contact Info

Product

Resources

About