SUPPRESSION OF MALIGNANCY BY THE 3' UNTRANSLATED REGIONS OF RIBONUCLEOTIDE REDUCTASE R1 AND R2 MESSENGER-RNAS

Mammalian ribonucleotide reductase is rate limiting for the synthesis of DNA. The active enzyme is composed of two dissimilar components cal led R1 and R2, encoded by different genes. The 3' untranslated regions (3' UTRs) of R1 and R2 messages contain sequences that are important in regulating gene expression through changes in message stability. We have constructed expression plasmids containing the R1 or R2 mRNA 3' UTRs, and we show that transfection of these plasmids into highly mali gnant mouse 10T1/2 cells significantly suppresses the tumorigenic prop erties of these cells in syngeneic mice when compared with cells trans fected with the same plasmid lacking R1 or R2 3' UTR sequences or when compared with cells transfected with the same plasmid expressing a he terologous sequence as a control. Furthermore, cells expressing the R2 3' UTR exhibit significantly reduced potential to disseminate to the lungs of syngeneic animals in experimental metastasis assays. The tumo r-suppressive effects of the mouse R1 and R2 3' UTRs were not confined to mouse cells, because human HeLa cells transfected with expression plasmids containing either R1 or R2 3' UTRs mere also significantly le ss tumorigenic in assays using BALB/c nu/nu mice. These studies demons trate that the untranslated regions of ribonucleotide reductase mRNAs can function as modifiers of tumor cell development and for the more c omplex process of tumor dissemination. We propose that these malignanc y-suppressive effects are mediated through RNA interactions with cellu lar components involved in growth regulation through mechanisms of pos ttranscriptional control of gene expression. In addition, these observ ations emphasize the enormous potential of untranslated RNA to act dir ectly as modifiers of biological characteristics relevant to mechanism s of malignancy.