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Kaiso-deficient mice show resistance to intestinal cancer.
- Mol. Cell. Biol.
, 2006
"... Kaiso is a BTB domain protein that associates with the signaling molecule p120-catenin and binds to the methylated sequence mCGmCG or the nonmethylated sequence CTGCNA to modulate transcription. In Xenopus laevis, xKaiso deficiency leads to embryonic death accompanied by premature gene activation i ..."
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Kaiso is a BTB domain protein that associates with the signaling molecule p120-catenin and binds to the methylated sequence mCGmCG or the nonmethylated sequence CTGCNA to modulate transcription. In Xenopus laevis, xKaiso deficiency leads to embryonic death accompanied by premature gene activation in blastulae and upregulation of the xWnt11 gene. Kaiso has also been proposed to play an essential role in mammalian synapsespecific transcription. We disrupted the Kaiso gene in mice to assess its role in mammalian development. Kaiso-null mice were viable and fertile, with no detectable abnormalities of development or gene expression. However, when crossed with tumor-susceptible Apc Min/؉ mice, Kaiso-null mice showed a delayed onset of intestinal tumorigenesis. Kaiso was found to be upregulated in murine intestinal tumors and is expressed in human colon cancers. Our data suggest that Kaiso plays a role in intestinal cancer and may therefore represent a potential target for therapeutic intervention.
Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease. Cancer Res
, 2005
"... We examined the expression and localization of p120 catenin (p120ctn) as a consequence of the epithelial to mesenchymal transition (EMT) of highly differentiated colon carcinoma cells (LIM1863 cells). This unique line grows in suspension as spheroids and undergoes an EMT within 24 hours following st ..."
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We examined the expression and localization of p120 catenin (p120ctn) as a consequence of the epithelial to mesenchymal transition (EMT) of highly differentiated colon carcinoma cells (LIM1863 cells). This unique line grows in suspension as spheroids and undergoes an EMT within 24 hours following stimulation with transforming growth factor-B and tumor necrosis factor-A. Although p120ctn expression remains stable during the EMT, its localization shifts from cell-cell junctions to the cytoplasm. Interestingly, a marked decrease in RhoA activation coincident with E-cadherin loss occurs during the EMT and correlates with the formation of a p120ctn/RhoA complex. Use of RNA interference showed that p120ctn reduction results in increased RhoA activity and a significant decrease in the motility of post-EMT cells. To determine the relevance of these findings to colorectal cancer progression, we assessed p120ctn expression by immunohistochemistry in 557 primary tumors. Of note, we observed that 53 % of tumors presented cytoplasmic staining for p120ctn, and statistical analysis revealed that this localization is predictive of poor patient outcome. Cytoplasmic p120ctn correlated with later-stage tumors, significantly reduced 5- and 10-year survival times and a greater propensity for metastasis to lymph nodes compared with junctional p120ctn. We also confirmed that altered localization of p120ctn corresponded with loss or cytoplasmic localization of E-cadherin. These alterations in E-cadherin are also associated with a significant reduction in patient survival time and an increase in tumor stage and lymph node metastasis. These data provide a compelling argument for the importance of both p120ctn and the EMT itself in the progression of colorectal carcinoma. (Cancer Res 2005; 65(23): 10938-45)
Adenoma Formation following Limited Ablation of p120- Catenin in the Mouse Intestine
"... p120 loss destabilizes E-cadherin and could therefore result in tumor and/or metastasis-promoting activities similar to those caused by E-cadherin downregulation. Previously, we reported that p120 is essential in the intestine for barrier function, epithelial homeostasis and survival. Conditional p1 ..."
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p120 loss destabilizes E-cadherin and could therefore result in tumor and/or metastasis-promoting activities similar to those caused by E-cadherin downregulation. Previously, we reported that p120 is essential in the intestine for barrier function, epithelial homeostasis and survival. Conditional p120 ablation in the mouse intestine induced severe inflammatory bowel disease, but long-term cancer-related studies were impossible because none of the animals survived longer than 21 days. Here, we used a tamoxifen-inducible mouse model (Vil-Cre-ERT2;p120fl/fl) to limit the extent of p120 ablation and thereby enable long-term studies. Reducing p120 KO to,10 % of the intestinal epithelium produced long-lived animals outwardly indistinguishable from controls. Effects of prolonged p120 absence were then evaluated at intervals spanning 2 to 18 months. At all time points, immunostaining revealed microdomains of p120-null epithelium interspersed with normal epithelium. Thus, stochastic p120 ablation is compatible with crypt progenitor cell function and permitted lifelong renewal of the p120-null cells. Consistent with previous observations, a barrier defect and frequent infiltration of neutrophils was observed, suggesting that focal p120 loss generates a microenvironment disposed to chronic inflammation. We report that 45 % of these animals developed tumors within 18 months of tamoxifen induction. Interestingly, b-catenin was upregulated
Dynamic and Static Interactions between p120 Catenin and E-Cadherin Regulate the Stability of Cell-Cell Adhesion
"... The association of p120 catenin (p120) with the juxta-membrane domain (JMD) of the cadherin cyto-plasmic tail is critical for the surface stability of cadherin-catenin cell-cell adhesion complexes. Here, we present the crystal structure of p120 iso-form 4A in complex with the JMD core region (JMDcor ..."
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The association of p120 catenin (p120) with the juxta-membrane domain (JMD) of the cadherin cyto-plasmic tail is critical for the surface stability of cadherin-catenin cell-cell adhesion complexes. Here, we present the crystal structure of p120 iso-form 4A in complex with the JMD core region (JMDcore) of E-cadherin. The p120 armadillo repeat domain contains modular binding pockets that are complementary to electrostatic and hydrophobic properties of the JMDcore. Single-residue mutations within the JMDcore-binding site of p120 abolished its interaction with E- and N-cadherins in vitro and in cultured cells. These mutations of p120 enabled us to clearly differentiate between N-cadherin-dependent and-independent steps of neuronal dendritic spine morphogenesis crucial for synapse development. NMR studies revealed that p120 regu-lates the stability of cadherin-mediated cell-cell adhesion by associating with the majority of the JMD, including residues implicated in clathrin-medi-ated endocytosis and Hakai-dependent ubiquitina-tion of E-cadherin, through its discrete ‘‘dynamic’’ and ‘‘static’ ’ binding sites.
p120-Catenin Is a Key Component of the
, 2008
"... p120-catenin is a key component of the cadherin–γ-secretase supercomplex ..."
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doi:10.1155/2010/616023 Clinical Study The Prognostic Impact of Protein Expression of E-Cadherin-Catenin Complexes Differs between Rectal
, 2010
"... which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The E-cadherin-catenin complex provides cell-cell adhesion. In order for a carcinoma to metastasize, cancer cells must let go of their hold of neighboring cells in the primary ..."
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which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The E-cadherin-catenin complex provides cell-cell adhesion. In order for a carcinoma to metastasize, cancer cells must let go of their hold of neighboring cells in the primary tumor. The presence of components of the E-cadherin-catenin complex in 246 rectal adenocarcinomas was examined by immunohistochemistry and compared to their presence in 219 colon carcinomas. The expression data were correlated to clinical information from the patients ’ records. There were statistically significant differences in protein expression between the rectal and the colon carcinomas regarding membranous β-catenin, γ-catenin, p120-catenin, and E-cadherin, as well as nuclear β-catenin. In the rectal carcinomas, there was a significant inverse association between the expression of p120-catenin in cell membranes of the primary tumors and the occurrence of local recurrence, while membranous protein expression of β-catenin was inversely related to distant metastases. 1.
susceptibility: from the laboratory to clinical practice
, 2003
"... The role of the E-cadherin gene (CDH1) in diffuse gastric cancer ..."
Departments of Pathology and Dermatology and
"... p120 catenin associates with kinesin and facilitates the transport of cadherin–catenin complexes to intercellular junctions ..."
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p120 catenin associates with kinesin and facilitates the transport of cadherin–catenin complexes to intercellular junctions
