Factors affecting the mRNA levels for the non-heme iron and effector-binding subunits of ribonucleotide reductase.
Ribonucleotide reductase which catalyzes the rate-limiting step in the de novo synthesis of dNTPs is composed of two non-identical protein subunits which are not under coordinate control in terms of synthesis and degradation. The mRNAs for the effector-binding (EB) and non-heme iron (NHI) subunits are likewise not under coordinate control during cell cycle traverse. Inhibitors directed at the specific subunits of ribonucleotide reductase block DNA synthesis. These current studies show that drugs such as IMPY or hydroxyurea which specifically inhibit the NHI subunit cause a marked increase in the steady-state level of the mRNA for the NHI subunit while resulting in a decrease in the level of mRNA for the EB subunit. In cells treated with deoxyadenosine, the patterns of the mRNAs for the NHI and EB subunits were different from those seen in the IMPY- or hydroxyurea-treated cells. Control experiments utilizing inhibitors (aphidicolin or araC) directed at DNA polymerase showed that the pattern of changes in the mRNA levels for the NHI and EB subunits were specific for the reductase inhibitors. These changes in the mRNAs for the NHI and EB subunits may be due to drug-induced alterations in transcription rates and/or degradation rates for the specific mRNAs.
Carter
G L
GL
Department of Biochemistry, East Carolina University School Of Medicine, Greenville, NC 27858.
Cory
J G
JG
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006918:Hydroxyurea / Q000494:pharmacology; D007939:Leukemia L1210; D008667:Metalloproteins / Q000378:metabolism*; D019159:Nonheme Iron Proteins; D014176:Protein Biosynthesis / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D003839:Deoxyadenosines; D008667:Metalloproteins; D019159:Nonheme Iron Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D003561:Cytarabine; D003609:Dactinomycin; D003513:Cycloheximide; D012264:Ribonucleotide Reductases; C000971:2,3-dihydro-1H-imidazo(1,2-b)pyrazole; D002118:Calcium; D006918:Hydroxyurea