Oncogenic Raf-1 Disrupts Epithelial Tight Junctions via Downregulation of Occludin

doi:10.1083/jcb.148.4.791

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© The Rockefeller University Press, 0021-9525/2000/2/791/ $5.00
The Journal of Cell Biology, Volume 148, Number 4, February 21, 2000 791-800

Original Article

Oncogenic Raf-1 Disrupts Epithelial Tight Junctions via Downregulation of Occludin

Danxi Li^a and Randall J. Mrsny^a
^a Department of Pharmaceutical Research and Development, Genentech Inc., South San Francisco, California 94080

Correspondence to: Randall J. Mrsny, Genentech Inc., MS #6, 1 DNA Way, South San Francisco, CA 94080. Tel:(650) 225-2592 Fax:650-225-1418 E-mail:mrsny{at}gene.com.

Occludin is an integral membrane protein of the epithelial celltight junction (TJ). Its potential role in coordinating structuraland functional events of TJ formation has been suggested recently.Using a rat salivary gland epithelial cell line (Pa-4) as amodel system, we have demonstrated that occludin not only isa critical component of functional TJs but also controls thephenotypic changes associated with epithelium oncogenesis. Transfectionof an oncogenic Raf-1 into Pa-4 cells resulted in a completeloss of TJ function and the acquisition of a stratified phenotypethat lacked cell–cell contact growth control. The expressionof occludin and claudin-1 was downregulated, and the distributionpatterns of ZO-1 and E-cadherin were altered. Introduction ofthe human occludin gene into Raf-1–activated Pa-4 cellsresulted in reacquisition of a monolayer phenotype and the formationof functionally intact TJs. In addition, the presence of exogenousoccludin 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 growthof Raf-1–activated Pa-4 cells in soft agarose. Thus, occludinmay act as a pivotal signaling molecule in oncogenic Raf- 1–induceddisruption of TJs, and regulates phenotypic changes associatedwith epithelial cell transformation.

Key Words: occludin, Raf-MEK-ERK signaling, tight junction, claudin-1,epithelium transformation

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