Genre
- Journal Article
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. (C) 1995 Wiley-Liss, Inc.
UNIV MANITOBA,MANITOBA INST CELL BIOL,WINNIPEG,MB R3E 0V9,CANADA. UNIV MANITOBA,DEPT BIOCHEM & MOLEC BIOL,WINNIPEG,MB R3E 0V9,CANADA.
NEW YORK; DIV JOHN WILEY & SONS INC 605 THIRD AVE, NEW YORK, NY 10158-0012
WILEY-LISS
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Source type: Electronic(1)
Language
- English
Subjects
- TGF-BETA(1)
- RESISTANCE
- MESSENGER-RNA STABILITY
- FACTOR-BETA
- METASTATIC PROGRESSION
- PROTEIN KINASE-C
- RIBONUCLEOTIDE REDUCTASE
- ABERRANT REGULATION
- MOUSE-CELL LINE
- FIBROBLASTS
- PERTUSSIS TOXIN
- Biochemistry & Molecular Biology
- HYDROXYUREA
- OKADAIC ACID
- Cell Biology
- TUMOR PROMOTERS
- METASTASIS