RB and c-Myc Activate Expression of the E-Cadherin Gene in Epithelial Cells through Interaction with Transcription Factor AP-2

Batsché, Éric; Muchardt, Christian; Behrens, Jürgen; Hurst, Helen C.; Crémisi, C

doi:10.1128/mcb.18.7.3647

Cited by 155 publications

(141 citation statements)

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“…Transfection with AP-2a upregulates E-cadherin expression As AP-2a is known to positively regulate the expression of E-cadherin (Batsche et al, 1998;West-Mays et al, 2003;Sumigama et al, 2004), we next examined the effect of AP-2a transfection on the expression of E-cadherin in SW480 cells. The results depicted in Figure 5a (Western blot) show that although the control SW480neo cells do not express E-cadherin (lane 1), the two AP-2a-transfected clones 1 and 2 express E-cadherin ( Figure 5a, lanes 2 and 3).…”

Section: Resultsmentioning

confidence: 99%

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

et al. 2007

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Activator protein-2 (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells and has been implicated in the acquisition of the metastatic phenotype in several types of cancer. Herein, we examine the role of AP-2a in colon cancer progression. We provide evidence for the lack of AP-2a expression in the late stages of colon cancer cells. Re-expression of the AP-2a gene in the AP-2a-negative SW480 colon cancer cells suppressed their tumorigenicity following orthotopic injection into the cecal wall of nude mice. The inhibition of tumor growth could be attributed to the increased expression of E-cadherin and decreased expression and activity of matrix-metalloproteinase-9 (MMP-9) in the transfected cells, as well as a substantial loss of their in vitro invasive properties. Conversely, targeting constitutive expression of AP-2a in AP-2-positive KM12C colon cancer cells with small interfering RNA resulted in an increase in their invasive potential, downregulation of E-cadherin and increased expression of MMP-9. In SW480 cells, re-expression of AP-2a resulted in a fourfold increase in the activity of E-cadherin promoter, and a 5-14-fold decrease in the activity of MMP-9 promoter, indicating transcriptional regulation of these genes by AP-2a. Chromatin immunoprecipitation assay showed that re-expressed AP-2a directly binds to the promoter of E-cadherin, where it has been previously reported to act as a transcriptional activator. Furthermore, chromatin immunoprecipitation assay revealed AP-2a binding to the MMP-9 promoter, which ensued by decreased binding of transcription factor Sp-1 and changes in the recruitment of transcription factors to a distal AP-1 element, thus, contributing to the overall downregulation of MMP-9 promoter activity. Collectively, our data provide evidence that AP-2a acts as a tumor suppressor gene in colon cancer.

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Section: Resultsmentioning

confidence: 99%

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

et al. 2007

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“…In addition to inhibiting gene transcription, pRB can stimulate gene transcription, through this promoting, amongst others, the transcription of the adhesion molecule E-cadherin (Batsche et al, 1998), the morphogen TGF beta 1 (Kim et al, 1992) and many lineage specific genes (Chen et al, 1996;Thomas et al, 2001). These findings infer a role for pRB in controlling cell homing and invasion, the paracrine management of tissue morphogenesis and the promotion of lineage specific differentiation.…”

Section: Introductionmentioning

confidence: 89%

“…Most noted is the function of pRB to control gene transcription via E2F (reviewed in Harbour and Dean, 2000;Stevens and La Thangue, 2003). Through association with specific members of this transcription factor family pRB represses genes required for cell cycle progression and proliferation, and by attracting additional chromatin modifying enzymes provokes chromatin modification, which may result in lasting repression of transcription and the establishment of permanent proliferation incompetence, typically seen in conjunction with senescence and terminal differentiation (Narita et al, 2003).In addition to inhibiting gene transcription, pRB can stimulate gene transcription, through this promoting, amongst others, the transcription of the adhesion molecule E-cadherin (Batsche et al, 1998), the morphogen TGF beta 1 (Kim et al, 1992) and many lineage specific genes (Chen et al, 1996;Thomas et al, 2001). These findings infer a role for pRB in controlling cell homing and invasion, the paracrine management of tissue morphogenesis and the promotion of lineage specific differentiation.…”

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confidence: 99%

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

et al. 2005

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Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spliced transcript is present in substantial amounts in peripheral blood of the patient and present evidence that the predicted protein product displays partial loss of activity reflecting in degree and presentation that of the partially penetrant RB1 missense mutant R661W. This infers that disease with reduced expressivity and incomplete penetrance may arise in individuals that carry the mutation and predicts such presentation for similar mutations with found in sporadic cases in the past. © 2004 Wiley-Liss, Inc.KEY WORDS: retinoblastoma; reduced expressivity; penetrance; splicing; RB1; pRB INTRODUCTIONRetinoblastoma, a childhood tumor of the eye, is caused by inactivation in the developing human retina of both alleles of the RB1 tumor suppressor gene (MIM# 180200) (reviewed in DiCiommo et al., 2000). In hereditary retinoblastoma (accounting for roughly 50% of cases) one RB1 allele is mutated in the germ line as either a novel or an inherited mutation. In this instance disease usually presents at an early age, with multiple tumor foci in both eyes, a high incidence of disease recurrence, increased lifetime risk for secondary malignancies and transmission to kindred with a penetrance of greater 95%. In its nonhereditary form mutational inactivation of both RB1 alleles DOI: 10.1002/humu.9305 2 Sánchez-Sánchez et al.arises from somatic events in a single retinal cell. Here disease presentation is far milder disease featuring late onset, single tumor foci in one eye only and absence of recurrence and secondary tumor development. In rare instance hereditary retinoblastoma can present in a form reminiscent to the non-hereditary disease (reduced expressivity), and often in this instance shows reduced penetrance in kindred (low penetrance).The product of the human RB1 gene (p110RB/pRB) is a nuclear phospho-protein composed of 928 amino acids. Through interacting with cellular proteins pRB influences cell proliferation, but also other types of cell behavior (reviewed in Kaelin, 1999;Zheng and Lee, 2001). Most noted is the function of pRB to control gene transcription via E2F (reviewed in Harbour and Dean, 2000;Stevens and La Thangue, 2003). Through association with specific members of this transcription factor family pRB represses genes required for cell cycle progression and proliferation, and by attracting additional chromatin modifyin...

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“…It was demonstrated that the retinoblastoma protein was able to induce E-cadherin expression. 62 In nearly all cases of SIL, human papilloma virus (HPV) is involved, and HPV protein E7 is able to inactivate the retinoblastoma protein. This could thus lead to a decreased activation of E-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

Changing Roles of Cadherins and Catenins during Progression of Squamous Intraepithelial Lesions in the Uterine Cervix

Boer

Dorst²,

Krieken

et al. 1999

The American Journal of Pathology

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Uterine cervix represents a convenient model for the study of the gradual transformation of normal squamous epithelium via low-to high-grade squamous intraepithelial lesions (SILs). Because SIL , on the basis of the cytokeratins expressed , are thought to originate from the reserve cells , we analyzed whether SILs also show a reserve cell phenotype with respect to intercellular interactions. The changes in expression and subcellular localization of the components of the adherens junction and desmosomal complexes were investigated in normal , metaplastic , and premalignant cervical epithelium , as well as in cell cultures derived from these tissues. The results suggest that 1) during progression of SILs , E-cadherin is suppressed, with its role in cell-cell connections diminishing; 2) P-cadherin , in contrast , becomes the predominant cadherin in high-grade SILs; 3) the level of cellular ␣-catenin is dramatically decreased in high-grade SILs; 4) the level of ␤-catenin is decreased during progression of SILs , with plakoglobin suggestively becoming the predominant catenin mediating connection of cadherins to the cytoskeleton; 5) the assembly of desmosomes is affected during progression of SILs and is accompanied by a dramatically decreased expression for desmogleins and desmoplakins (I , II); and 6) expression of differentiation markers (involucrin , CK13) in high-grade SILs seems to be controlled by P-cadherin as opposed to E-cadherin in the normal tissue counterpart. We conclude that during development of cervical lesions substantial (

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RB and c-Myc Activate Expression of the E-Cadherin Gene in Epithelial Cells through Interaction with Transcription Factor AP-2

Cited by 155 publications

References 52 publications

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

Changing Roles of Cadherins and Catenins during Progression of Squamous Intraepithelial Lesions in the Uterine Cervix

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