α-Catenin Inhibits β-Catenin Signaling by Preventing Formation of a β-Catenin·T-cell Factor·DNA Complex

Giannini, Ana L.M.; Vivanco, María dM; Kypta, Robert M.

doi:10.1074/jbc.m001929200

Cited by 89 publications

(107 citation statements)

References 44 publications

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“…23 Ctnna1 (a-catenin) also can block the interaction between the b-catenin/Tcf/DNA complex. 24 In addition, in agreement with our result, the reduced expression of a-catenin has been reported in several human cancers. 25 These data led us to investigate the abnormality of b-catenin protein expression in radiation-induced OS (Fig.…”

Section: Discussionsupporting

confidence: 82%

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

Daino

Ugolin

Altmeyer-Morel

et al. 2009

Intl Journal of Cancer

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To better understand the molecular basis of radiation-induced osteosarcoma (OS), we performed global gene expression profiling of rat OS tumors induced by the bone-seeking alpha emitter 238 Pu, and the expression profiles were compared with those of normal osteoblasts (OB). The expressions of 72 genes were significantly differentially expressed in the tumors related to OB. These included genes involved in the cell adhesion (e.g., Podxl, Col18a1, Cd93, Emcn and Vcl), differentiation, developmental processes (e.g., Hhex, Gata2, P2ry6, P2rx5, Cited2, Osmr and Igsf10), tumorsuppressor function (e.g., Nme3, Blcap and Rrm1), Src tyrosine kinase signaling (e.g., Hck, Shf, Arhgap29, Cttn and Akap12), and Wnt/b-catenin signaling (e.g., Fzd6, Lzic, Dkk3 and Ctnna1) pathways. Expression changes of several genes were validated by quantitative real-time RT-PCR analysis. Notably, all of the identified genes involved in the Wnt/b-catenin signaling pathway were known or proposed to be negative regulators of this pathway and were downregulated in the tumors, suggesting the activation of bcatenin in radiation-induced OS. By using immunohistochemical and immunoblot analyses, constitutive activation of the Wnt/b-catenin signaling pathway in the tumors was confirmed by observing nuclear and/or cytoplasmic localization of b-catenin and a decrease in its inactive (phosphorylated) form. Furthermore, we found a significant reduction in the levels of glycogen synthase kinase 3b (GSK-3b) protein in the tumors relative to OB. Taken together, these findings provide new insights into the molecular basis of radiation-induced OS. ' UICCKey words: osteosarcoma; osteoblast; ionizing radiation; carcinogenesis; transcriptome Osteosarcoma (OS) is the most common primary tumor of bone in children and adolescents. The peak incidence of OS occurs in the second decade of life, with an additional smaller peak in the elderly population. This tumor is highly aggressive and is thought to arise primarily from osteoblasts (OB), boneforming cells. An increased risk for developing OS is known to be associated with some genetic disorders, such as hereditary retinoblastoma and Li-Fraumeni syndrome with germline mutations in the retinoblastoma (RB1) and TP53 genes, respectively. 1,2 In agreement with this, abnormalities of genes involved in the RB1 and TP53 tumor-suppressor pathways are often found in OS. 3,4 On the other hand, the association between ionizing radiation and the subsequent development of OS has been well documented in prior studies. For example, OS is known as one of the most frequent secondary malignant neoplasms occurring within the radiation field in patients, especially with retinoblastoma, treated with radiation therapy. 1,5 The risk of OS has been reported to be increased following the internal exposure to bone-seeking radioisotopes from occupational or medicinal use. 6-8 Interestingly, some studies have revealed the genetic and cytogenetic changes in radiation-induced OS and suggested the presence of additional tumor-associated genes. ...

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Section: Discussionsupporting

confidence: 82%

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

Daino

Ugolin

Altmeyer-Morel

et al. 2009

Intl Journal of Cancer

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“…Upregulation of alpha-catenin could be an important mechanism of anti-carcinogenicity since alpha-catenin can act as an invasion suppressor [67]. Alpha-catenin expression in colon cancer cells is associated with an inhibition of TCF-dependent transcription [68]. Also, overexpression of plakophilin 2 in SW480 cells (human colon carcinoma cell line) caused an increase in β-catenin/TCF signaling [69].…”

Section: Discussionmentioning

confidence: 99%

Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer–related mechanisms in colon cancer cells in vitro

et al. 2004

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trum of possible biological actions of the bioactive compound quercetin is made using multiple gene expression analysis. Quercetin is a flavonoid that can inhibit proliferation of tumor cells and reduce the number of aberrant crypt foci, although increase of number of colon tumors was also reported. Aim of the study In order to elucidate possible mechanisms involved in its mode of action the effect of quercetin on expression of 4000 human genes in Caco-2 cells was studied and related to functional effects. Methods Caco-2 cells were exposed to 5 or 50 µM quercetin for 48 hours, differential expression of 4000 human genes was studied using microarrays and related to functional effects. Differentially expressed genes were categorized in seven functional groups: cell cycle and differentiation, apoptosis, tumor suppressor genes and oncogenes, cell adhesion and cell-cell interaction, transcription, signal transduction and energy metabolism. Also, cell proliferation and cell cycle distribution were measured. Results Quercetin (5 µM) downregulated expression of cell cycle genes (for example CDC6, CDK4 and cyclin D1), downregulated cell proliferation and induced cell cycle arrest in Caco-2 cells. After exposure to 50 µM quercetin cell proliferation decreased to 51.3 % of control, and further decrease of the percentage of cells in the G1 phase coincided with an increase of the percentage of cells in the sub-G1 phase. Quercetin upregulated expression of several tumor suppressor genes. In addition, genes involved in signal transduction pathways like beta catenin/ TCF signalling and MAPK signal transduction were influenced by quercetin. Conclusions This study shows that large-scale gene expression analysis in combination with functional assays yields a considerable amount of information on (anti-)carcinogenic potential of food components like quercetin.

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“…Transfection with ␣-catenin targeted to the nucleus inhibits transcription activity to the same extent as nontargeted ␣-catenin. Because ␣-catenin associated stably with the ␤-catenin-TCF complex, it was proposed that ␣-catenin may inhibit ␤-catenin-TCF transcription either by preventing DNA binding or by altering the ␤-catenin-TCF interactions with other proteins that regulate transcription in vivo (Giannini et al, 2000). Factors that regulate nuclear entry of ␣-catenin would link signaling events in the cytoplasm to ␤-catenin-dependent transcription in the nucleus.…”

Section: Nuclear Localization Of ␣-Cateninmentioning

confidence: 99%

“…Factors that regulate nuclear entry of ␣-catenin would link signaling events in the cytoplasm to ␤-catenin-dependent transcription in the nucleus. Giannini et al (2000), using immunofluorescence and confocal microscopy, reported nuclear localization of ␣-catenin in the cell line SW480 but not in HCT 116. However, in that study, confluent monolayers of HCT116 were examined, whereas the present study found ␣-catenin nuclear localization only in dispersed cells.…”

Section: Nuclear Localization Of ␣-Cateninmentioning

confidence: 99%

Variable Nuclear Localization of α-Catenin in Colorectal Carcinoma

El‐Bahrawy

Talbot

Poulsom

et al. 2002

Laboratory Investigation

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SUMMARY:The E-cadherin/catenin complex plays a major role in epithelial cell-cell adhesion. Both ␤-catenin and ␥-catenin bind directly to the cytoplasmic domain of E-cadherin whereas ␣-catenin links the bound ␤-catenin or ␥-catenin to the actin microfilament network of the cellular cytoskeleton. Significant changes in the expression and/or structure of members of the complex can occur in neoplasia. Several studies have reported on the nuclear localization of ␤-and ␥-catenin and on their role in influencing the transcriptional activity of several proto-oncogenes. The cellular localization of ␣-catenin has not been studied in detail. The aim of this study was to investigate the cellular localization of ␣-catenin in colorectal carcinoma both in vitro and in vivo and to assess whether it might be relevant to tumor behavior. The expression of ␣-catenin was examined in a panel of colorectal carcinoma cell lines (SW480, SW620, HCT116, HT29, and Caco-2) using a combination of immunohistochemistry, confocal fluorescence microscopy, and Western blotting. The expression of ␣-catenin was also studied by immunohistochemistry in 15 sporadic colorectal adenomas, 30 sporadic colorectal adenocarcinomas, and their 13 lymph node metastases. From familial adenomatous polyposis patients, 20 adenomas and 5 adenocarcinomas were studied. Nuclear localization of ␣-catenin was detected in the colorectal carcinoma cell lines when the cells were dispersed rather than confluent. ␣-catenin was not detected in the nuclei in any of the sporadic or familial adenomas. However, it was detected in one sporadic and one familial adenocarcinoma but not in any of the lymph node deposits. ␣-catenin can localize to the nuclei of colorectal tumor cells, and this may be related to lack of perception of connection to adjacent cells. (Lab Invest 2002, 82:1167-1174.

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α-Catenin Inhibits β-Catenin Signaling by Preventing Formation of a β-Catenin·T-cell Factor·DNA Complex

Cited by 89 publications

References 44 publications

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer–related mechanisms in colon cancer cells in vitro

Variable Nuclear Localization of α-Catenin in Colorectal Carcinoma

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