Malignant transformation by H‐ras results in aberrant regulation of ribonucleotide reductase gene expression by transforming growth factor‐β1

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.PT: J; CR: ALBERT DA, 1989, J CELL PHYSIOL, V138, P129 AMARA FM, 1993, NUCLEIC ACIDS RES, V21, P4803 AMARA FM, 1994, J BIOL CHEM, V269, P6709 BJORKLUND S, 1990, BIOCHEMISTRY-US, V29, P5452 BRUNNER AM, 1989, J BIOL CHEM, V264, P13660 CHAMBARD JC, 1987, NATURE, V326, P800 CHAN AK, 1993, BIOCHEMISTRY-US, V32, P12835 CHEN FY, 1993, EMBO J, V12, P3977 CHOY BK, 1989, BIOCHEM BIOPH RES CO, V162, P1417 COHEN P, 1990, TRENDS BIOCHEM SCI, V15, P98 CORY JG, 1972, CANCER RES, V32, P1301 EGAN SE, 1987, MOL CELL BIOL, V7, P830 EGAN SE, 1987, SCIENCE, V238, P202 FELGNER PL, 1987, P NATL ACAD SCI USA, V84, P7413 FISCHER JB, 1988, J BIOL CHEM, V263, P2808 GENTRY LE, 1988, MOL CELL BIOL, V8, P4162 GOUGH NM, 1988, ANAL BIOCHEM, V173, P93 GREENBERG AH, 1989, INVAS METAST, V9, P360 GRUPPUSO PA, 1991, J BIOL CHEM, V266, P3444 HARDS RG, 1981, J CELL PHYSIOL, V106, P309 HOWE PH, 1989, CANCER RES, V49, P6024 HURTA RAR, 1990, BIOCHIM BIOPHYS ACTA, V1087, P165 HURTA RAR, 1991, J BIOL CHEM, V266, P24897 HURTA RAR, 1992, BIOCH CELL BIOL, V70, P1081 HURTA RAR, 1992, J BIOL CHEM, V267, P7066 HURTA RAR, 1994, J CELL PHYSL, V158, P187 JAKOWLEW SB, 1988, ONCOGENE RES, V2, P135 KATAOKA R, 1993, J BIOL CHEM, V268, P19851 KIM SJ, 1990, MOL CELL BIOL, V10, P1492 LE AQ, 1992, J BIOL CHEM, V267, P1072 LEWIS WH, 1978, J CELL PHYSL, V94, P287 LUTTRELL LM, 1988, J BIOL CHEM, V263, P6134 MCCLARTY GA, 1986, SOMAT CELL MOLEC GEN, V12, P121 MCCLARTY GA, 1987, BIOCHEMISTRY-US, V26, P8004 MCCLARTY GA, 1990, J BIOL CHEM, V265, P7539 MUKHERJEE R, 1987, J BIOL CHEM, V262, P13697 NICOLSON GL, 1984, CANCER METAST REV, V3, P25 NISHIZUKA Y, 1986, SCIENCE, V233, P305 PELECH SL, 1990, BIOCHEM CELL BIOL, V68, P1297 PENTTINEN RP, 1988, P NATL ACAD SCI USA, V85, P1105 PERTOVAARA L, 1989, MOL CELL BIOL, V9, P1255 PHILLIPS DR, 1986, BIOCHEMISTRY-US, V25, P7355 RAGHOW R, 1987, TRENDS BIOCHEM SCI, V12, P358 RALPH RK, 1990, BIOESSAYS, V12, P121 ROBERTS AB, 1988, BRIT J CANCER, V57, P594 SAMUEL SK, 1992, EMBO J, V11, P1599 SASSA T, 1989, BIOCHEM BIOPH RES CO, V159, P939 SCHWARZ LC, 1988, CANCER RES, V48, P6999 SCHWARZ LC, 1990, GROWTH FACTORS, V3, P115 SPORN MB, 1990, CELL REGUL, V1, P875 STEEPER JR, 1970, ANAL BIOCHEM, V34, P123 TAMM I, 1978, ADV VIRUS RES, P187 THELANDER L, 1980, J BIOL CHEM, V255, P7426 ULLMAN B, 1979, P NATL ACAD SCI USA, V76, P1074 WAKEFIELD LM, 1987, J CELL BIOL, V105, P965 WEBER G, 1983, CANCER RES, V43, P3466 WEINBERG G, 1981, P NATL ACAD SCI USA, V78, P2447 WEINBERG RA, 1989, ONCOGENES MOL ORIGIN, P46 WILDER PJ, 1991, CANCER RES, V51, P5898 WRIGHT JA, 1989, INT ENCY PHARM THERA, V128, P89 WRIGHT JA, 1990, ANTICANCER RES, V10, P1247 WRIGHT JA, 1990, BIOCH CELL BIOL, V68, P1364 WRIGHT JA, 1993, CRIT REV ONCOGENESIS, V4, P473 YOUNG S, 1987, BIOCHEM J, V244, P775; NR: 64; TC: 25; J9: J CELL BIOCHEM; PG: 14; GA: QJ118Source type: Electronic(1