THE MAMMALIAN RIBONUCLEOTIDE REDUCTASE R2 COMPONENT COOPERATES WITH AVARIETY OF ONCOGENES IN MECHANISMS OF CELLULAR-TRANSFORMATION

Ribonucleotide reductase, which is composed of the two protein compone nts R1 and R2, is a highly regulated enzyme activity that is essential for DNA synthesis and repair. Recent studies have shown that elevated expression of the rate-limiting R2 component increases Raf-l protein activation and mitogen-activated protein kinase activity and acts as a novel malignancy determinant in cooperation with H-ras and rac-1, We show that R2 cooperation in cellular transformation extends to a varie ty of oncogenes with different functions and cellular locations. Ancho rage-independent growth of cells transformed with v-fms, v-src, A-raf, v-fes, c-myc, and ornithine decarboxylase was markedly enhanced when the R2 component of ribonucleotide reductase was overexpressed, In add ition, we observed that elevated R2 expression conferred on c-myc-tran sformed NIH 3T3 cells an increased tumorigenic potential in immunoinco mpetent mice. Taken together, these observations demonstrate that the R2 protein is not only a rate-limiting component for ribonucleotide re duction but that it is also capable of acting in cooperation with a va riety of oncogenes to determine transformation and tumorigenic potenti al.