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The Mammalian Ribonucleotide Reductase R2 Component Cooperates with a Variety of Oncogenes in Mechanisms of Cellular Transformation¹

Manitoba Institute of Cell Biology and the University of Manitoba, Winnipeg, Manitoba, R3E 0V9 Canada

Ribonucleotide reductase, which is composed of the two protein components 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-1 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 variety of oncogenes with different functions and cellular locations. Anchorage-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 addition, we observed that elevated R2 expression conferred on c-myc-transformed NIH 3T3 cells an increased tumorigenic potential in immunoincompetent mice. Taken together, these observations demonstrate that the R2 protein is not only a rate-limiting component for ribonucleotide reduction but that it is also capable of acting in cooperation with a variety of oncogenes to determine transformation and tumorigenic potential.

¹ Supported by National Cancer Institute (Canada) and NSERC operating grants (to J. A. W.). H. F. has been a recipient of a MRC postdoctoral fellowship and a MRC/Pfizer postdoctoral fellowship. J. A. W. is a Terry Fox Senior Scientist of the National Cancer Institute (Canada).

² To whom requests for reprints should be addressed, at Manitoba Institute of Cell Biology and the University of Manitoba, 100 Olivia Street. Winnipeg, Manitoba, R3E 0V9 Canada. Phone: (204) 787-4128; Fax: (204) 787-2190.

Received 2/10/98. Accepted 2/27/98.

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