Altered regulation of message stability and tumor promoter-responsive cis-trans interactions of ribonucleotide reductase R1 and R2 messenger RNAs in hydroxyurea-resistant cells

Mammalian ribonucleotide reductase is a highly regulated activity essential for DNA synthesis and repair. The activity and message levels of the enzyme are elevated in cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, and this appears to be mediated through specific cis elements in the 3'-untranslated region of the R1 and R2 mRNAs that interact with R1 and R2 binding proteins called R1BP and R2BP, respectively. Hydroxyurea-resistant cells with increased R1 and R2 message levels were observed to have increased R1 and R2 message half-lives. This was accompanied by alterations in R1 and R2 3'-untranslated region cis-trans interactions, as judged by band shift and UV crosslinking assays, in which R1BP and R2BP binding was markedly reduced. This first description of mutant mammalian cells altered in message stability regulatory determinants indicates another mechanism for acquiring resistance to an antitumor agent. Furthermore, the present study strongly supports the concept that R1BP and R2BP are important general regulators of ribonucleotide reductase message stability and act as message destabilizing factors.PT: J; CR: AMARA FM, 1994, J BIOL CHEM, V269, P6709 AMARA FM, 1995, NUCLEIC ACIDS RES, V23, P1461 BRUCE AG, 1978, NUCLEIC ACIDS RES, V5, P3665 CHEN FY, 1993, EMBO J, V12, P3977 CHEN FY, 1994, BIOCHEM J, V302, P125 CHEN FY, 1994, NUCLEIC ACIDS RES, V22, P4796 DAVID PJ, 1992, J BIOL CHEM, V267, P24103 FOULKES NS, 1992, CELL, V68, P411 GOUGH NM, 1988, ANAL BIOCHEM, V173, P93 HENDERSON BR, 1993, J BIOL CHEM, V268, P27327 HURTA RAR, 1990, BIOCHIM BIOPHYS ACTA, V1087, P165 HURTA RAR, 1992, J BIOL CHEM, V267, P7066 HURTA RAR, 1995, J CELL BIOCHEM, V57, P543 KUO ML, 1995, CANCER RES, V55, P2800 MCCLARTY GA, 1986, CANCER RES, V46, P4516 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 ROSS J, 1995, IN PRESS MICROBIOL R SACHS AB, 1993, CELL, V74, P413 STUBBE JA, 1989, ANNU REV BIOCHEM, V58, P257 WEBER G, 1983, CANCER RES, V43, P3466 WRIGHT JA, 1989, INT ENCY PHARM THERA, V128, P89 WRIGHT JA, 1990, BIOCH CELL BIOL, V68, P1364 ZAIDI SHE, 1994, J BIOL CHEM, V269, P24000; NR: 26; TC: 15; J9: CANCER RES; PG: 4; GA: RZ069Source type: Electronic(1