WILD-TYPE NEU TRANSGENE COUNTERACTS MUTANT HOMOLOG IN MALIGNANT TRANSFORMATION OF RAT SCHWANN-CELLS

Mutational activation of the neu (erbB-2) receptor protein tyrosine ki nase gene appears to be the triggering event in the process of oncogen esis induced by N-ethyl-N-nitrosourea (EtNU) in immature Schwann cells of the rat peripheral nervous system. Subsequent loss of the wild-typ e neu allele may represent a critical secondary step towards malignanc y. Developmentally-regulated expression of a wild-type rat neu transge ne (neu cDNA under the control of the rat P-o promotor) in the Schwann cells of transgenic BDIX and Sprague-Dawley rats exposed to EtNU on p ostnatal day 1 results in a lower incidence of early atypical prolifer ates in the trigeminal nerve. Furthermore, re-introduction of the wild -type neu gene into homozygous neu mutant schwannoma cells counteracts the expression of the tumorigenic phenotype. The suppressive action o f the wild-type gene over its mutationally activated oncogenic homolog ue underlines the critical function of the neu gene in the control of differentiation in the Schwann cell lineage, and provides evidence for the responsiveness of cellular phenotypes towards quantitative shifts in the dosage of wild-type vs mutant signal transducing molecules.