The mammalian ribonucleotide reductase R2 component cooperates with a variety of oncogenes in mechanisms of cellular transformation.
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.
Fan
H
H
Manitoba Institute of Cell Biology and the University of Manitoba, Winnipeg, Canada.
Villegas
C
C
Huang
A
A
Wright
J A
JA
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D015681:Fusion Proteins, gag-onc / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016281:Oncogene Protein gp140(v-fms) / Q000502:physiology; D015688:Oncogene Protein pp60(v-src) / Q000502:physiology; D009955:Ornithine Decarboxylase / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D012264:Ribonucleotide Reductases / Q000378:metabolism / Q000502:physiology*; D014410:Tumor Stem Cell Assay
D015681:Fusion Proteins, gag-onc; D016281:Oncogene Protein gp140(v-fms); D016271:Proto-Oncogene Proteins c-myc; D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit; D015688:Oncogene Protein pp60(v-src); D019908:Proto-Oncogene Proteins c-raf; D009955:Ornithine Decarboxylase