Oncogenic Raf-1 disrupts epithelial tight junctions via downregulation of occludin

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Abstract

Occludin is an integral membrane protein of the epithelial cell tight junction (TJ), Its potential role in coordinating structural and functional events of TJ formation has been suggested recently. Using a rat salivary gland epithelial cell line (Pa-4) as a model system, we have demonstrated that occludin not only is a critical component of functional TJs but also controls the phenotypic changes associated with epithelium oncogenesis. Transfection of an oncogenic Raf-l into Pa-4 cells resulted in a complete loss of TJ function and the acquisition of a stratified phenotype that lacked cell-cell contact growth control. The expression of occludin and claudin-1 was downregulated, and the distribution patterns of ZO-1 and E-cadherin were altered. Introduction of the human occludin gene into Raf-1-activated Pa-4 cells resulted in reacquisition of a monolayer phenotype and the formation of functionally intact TJs. In addition, the presence of exogenous occludin protein led to a recovery in claudin-1 protein level, relocation of the zonula occludens 1 protein (ZO-1) to the TJ, and redistribution of E-cadherin to the lateral membrane. Furthermore, the expression of occludin inhibited anchorage-independent growth of Raf-l-activated Pa-4 cells in soft agarose, Thus, occludin may act as a pivotal signaling molecule in oncogenic Raf-1-induced disruption of TJs, and regulates phenotypic changes associated with epithelial cell transformation.
Original languageEnglish
Pages (from-to)791-800
Number of pages10
JournalThe Journal of Cell Biology (JCB)
Volume148
Issue number4
Publication statusPublished - 2000

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Occludin
Tight Junctions
Down-Regulation
Zonula Occludens-1 Protein
Claudin-1
Epithelial Cells
Cadherins
Claudins
Phenotype
Intercellular Junctions
Growth
Salivary Glands
Sepharose
Transfection
Membrane Proteins
Carcinogenesis
Epithelium
Cell Line
Membranes

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Oncogenic Raf-1 disrupts epithelial tight junctions via downregulation of occludin. / Li, D X; Mrsny, Randall J.

In: The Journal of Cell Biology (JCB), Vol. 148, No. 4, 2000, p. 791-800.

Research output: Contribution to journalArticle

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abstract = "Occludin is an integral membrane protein of the epithelial cell tight junction (TJ), Its potential role in coordinating structural and functional events of TJ formation has been suggested recently. Using a rat salivary gland epithelial cell line (Pa-4) as a model system, we have demonstrated that occludin not only is a critical component of functional TJs but also controls the phenotypic changes associated with epithelium oncogenesis. Transfection of an oncogenic Raf-l into Pa-4 cells resulted in a complete loss of TJ function and the acquisition of a stratified phenotype that lacked cell-cell contact growth control. The expression of occludin and claudin-1 was downregulated, and the distribution patterns of ZO-1 and E-cadherin were altered. Introduction of the human occludin gene into Raf-1-activated Pa-4 cells resulted in reacquisition of a monolayer phenotype and the formation of functionally intact TJs. In addition, the presence of exogenous occludin protein led to a recovery in claudin-1 protein level, relocation of the zonula occludens 1 protein (ZO-1) to the TJ, and redistribution of E-cadherin to the lateral membrane. Furthermore, the expression of occludin inhibited anchorage-independent growth of Raf-l-activated Pa-4 cells in soft agarose, Thus, occludin may act as a pivotal signaling molecule in oncogenic Raf-1-induced disruption of TJs, and regulates phenotypic changes associated with epithelial cell transformation.",
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AB - Occludin is an integral membrane protein of the epithelial cell tight junction (TJ), Its potential role in coordinating structural and functional events of TJ formation has been suggested recently. Using a rat salivary gland epithelial cell line (Pa-4) as a model system, we have demonstrated that occludin not only is a critical component of functional TJs but also controls the phenotypic changes associated with epithelium oncogenesis. Transfection of an oncogenic Raf-l into Pa-4 cells resulted in a complete loss of TJ function and the acquisition of a stratified phenotype that lacked cell-cell contact growth control. The expression of occludin and claudin-1 was downregulated, and the distribution patterns of ZO-1 and E-cadherin were altered. Introduction of the human occludin gene into Raf-1-activated Pa-4 cells resulted in reacquisition of a monolayer phenotype and the formation of functionally intact TJs. In addition, the presence of exogenous occludin protein led to a recovery in claudin-1 protein level, relocation of the zonula occludens 1 protein (ZO-1) to the TJ, and redistribution of E-cadherin to the lateral membrane. Furthermore, the expression of occludin inhibited anchorage-independent growth of Raf-l-activated Pa-4 cells in soft agarose, Thus, occludin may act as a pivotal signaling molecule in oncogenic Raf-1-induced disruption of TJs, and regulates phenotypic changes associated with epithelial cell transformation.

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