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

Original Article

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



Danxi Lia and Randall J. Mrsnya

a Department of Pharmaceutical Research and Development, Genentech Inc., South San Francisco, California 94080
Genentech Inc., MS #6, 1 DNA Way, South San Francisco, CA 94080.650-225-1418(650) 225-2592

mrsny{at}gene.com

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-1 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-1–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.

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

© 2000 The Rockefeller University Press

Abbreviations used in this paper: AJ, adherens junction; ERK, extracellular-regulated kinase; MEK, mitogen-activated protein kinase; TEER, transepithelial electrical resistance; TJ, tight junction; ZO-1, zonula occludens 1.


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