Iransgenic mice expressing; the Pol vom a Middle I antigen (PyM 1 ) or newborn mice infected with PyMT rapidly develop endothelial tumors or hemangiomas. In addition, primary endothelial relis are easily transformed by PyMT in a single step process. This predilection for endoihelial cells and apparent single step transformation suggests that PyMT is uniquely able to subvert im portant endotheüal signal transduction pathways. To study the mechanism of 'his transformation we have used the mouse brain endolhelial cell line jbLND i) expressing mutants of the small GTPase Rac from a tetracycline regulated promoter. Control celts demonstrate a loss of normal growth control, display aberrant morpho&enetic behaviour in vitro and are tumorigenic.This is accompanied by changes in cell shape with the formation of long filopodia and pHeiidopodia and an increase in both actin stress fibres and focal adhesions, hxpression of dominant negative Rar(N17Rac) inhibits proliferation with ac ( um illation of cells in GO/CI phases of the cell cycle.Capillary tube form at ion in matrigel is partially restored and tumor formation, after injection into nude mire, is inhibited. Surprisingly, no effect of N 17 Rac. expression is observed on the actin rytoskeleton of bEND cells suggesting that specifn downstream effectors of Rac are activated in these cells. These results illustarte an essential role for Rac in PyMT transformation of eridothelial cells and suggest thnt Rac rnav play an important role in the regulation of endothelial proliferation and morphogenesis.
|State||Published - Dec 1 1997|