Malignant transformation by H-ras results in aberrant regulation of ribonucleotide reductase gene expression by transforming growth factor-beta 1.
Ribonucleotide reductase is a key rate-limiting and regulatory step in DNA synthesis and plays a crucial role in the coordination of DNA synthesis, DNA repair, and cell proliferation. The present study demonstrates a link between alterations in TGF-beta 1 regulation during malignant conversion and the expression of ribonucleotide reductase. H-ras-transformed mouse 10T1/2 cell lines exhibiting malignant potential were examined for possible TGF-beta 1-mediated alterations in ribonucleotide reductase expression. Selective induction of ribonucleotide reductase gene expression occurred, since only H-ras-transformed highly metastatic cells exhibited marked elevations in ribonucleotide reductase expression, whereas nontransformed normal 10T1/2 cells were unaffected by TGF-beta 1 treatment. These changes occurred without any detectable modifications in DNA synthesis rates, suggesting that these changes were regulated by a novel mechanism independent of the S-phase of the cell cycle. Furthermore, this TGF-beta 1-mediated regulation of ribonucleotide reductase expression was shown to occur through an autocrine mechanism. TGF-beta 1-modulated regulation of ribonucleotide reductase expression requires de novo protein synthesis and involves, at least in part, transcriptional and post-transcriptional events. Furthermore, evidence is presented to suggest a possible role for protein kinase C-mediated events, protein phosphatases, and G-protein-coupled events in the TGF-beta 1-mediated regulation of ribonucleotide reductase expression in H-ras-transformed malignant cells. TGF-beta 1 regulation of ribonucleotide reductase in highly malignant cells appears to be complex and multifaceted and constitutes an integral part of an altered growth regulatory program.
Hurta
R A
RA
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.
Wright
J A
JA
D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005354:Fibrosarcoma / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D011905:Genes, ras; D051379:Mice; D012264:Ribonucleotide Reductases / Q000235:genetics*; D016196:S Phase / Q000235:genetics; D014162:Transfection / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016212:Transforming Growth Factor beta; D012264:Ribonucleotide Reductases