ORNITHINE DECARBOXYLASE TRANSFORMATION OF NIH 3T3 CELLS IS MEDIATED BY ALTERED EPIDERMAL GROWTH-FACTOR RECEPTOR ACTIVITY/

Ornithine decarboxylase (ODC) has been shown to be oncogenic in transf ected NIH/3T3 cells overexpressing the enzyme from a heterologous prom oter. These cells, designated as NODC-2 cells, acquire proliferative p roperties associated with tumorigenic transformation such as loss of c ontact inhibition, decreased population doubling time, anchorage-indep endent growth, and tumor production in nude mice, At least one of thes e parameters, loss of contact inhibition, remains dependent on elevate d ODC levels. We have used these cells to investigate the molecular me chanisms by which ODC overexpression drives cell transformation and to examine the involvement of other proto-oncogene products in this proc ess, An interaction between ODC overexpression and the epidermal growt h factor receptor (EGF-R) was suggested initially by the elevation of both basal (300%) and ligand-induced (457%) EGF-R tyrosine kinase acti vities in NODC-2 cells compared to similarly treated control NLK cells . Disruption of EGF-R mediated signal transduction in NODC-2 cells bot h by treatment with tyrphostin-25 or by transfection with a vector exp ressing a dominant negative EGF-R mutant resulted in reacquisition of contact-inhibited growth and suppression of anchorage-independent, clo nogenic growth in soft agar, We conclude that ODC-induced transformati on of NIH/3T3 cells is mediated, at least partly, by alterations in EG F-R signal transduction activity.