| Translational regulation of ribonucleotide reductase by eukaryotic initiation factor 4E links protein synthesis to the control of DNA replication. | |
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MedLine Citation:
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PMID: 10585489 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Ribonucleotide reductase synthesizes dNDPs, a specific and limiting step in DNA synthesis, and can participate in neoplastic transformation when overexpressed. The small subunit (ribonucleotide reductase 2 (RNR2)) was cloned as a major product in a subtraction library from eukaryotic initiation factor 4E (eIF4E)-transformed cells (Chinese hamster ovary-4E (CHO-4E)). CHO-4E cells have 20-40-fold elevated RNR2 protein, reflecting an increased distribution of RNR2 mRNA to the heavy polysomes. CHO-4E cells display an altered cell cycle with shortened S phase, similar to cells selected for RNR2 overexpression with hydroxyurea. The function of ribonucleotide reductase as a checkpoint component of S progression was studied in yeast in which elevated eIF4E rescued S-arrested rnr2-68(ts) cells, by increasing recruitment of its mRNA to polysomes. Crosses between rnr2-68(ts) and mutant eIF4E (cdc33-1(ts)) engendered conditional synthetic lethality, with extreme sensitivity to hydroxyurea and the microtubule depolymerizing agent, benomyl. The double mutant (cdc33-1 rnr2-68) also identified a unique terminal phenotype, arrested with small bud and a randomly distributed single nucleus, which is distinct from those of both parental single mutants. This phenotype defines eIF4E and RNR2 as determinants in an important cell cycle checkpoint, in early/mid-S phase. These results also provide a link between protein and DNA synthesis and provide an explanation for cell cycle alterations induced by elevated eIF4E. |
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Authors:
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M R Abid; Y Li; C Anthony; A De Benedetti |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 274 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 1999 Dec |
Date Detail:
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Created Date: 2000-01-13 Completed Date: 2000-01-13 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 35991-8 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Louisiana State University Medical Center, Shreveport, Louisiana 71130-3932, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Benomyl / pharmacology CHO Cells Cell Cycle / physiology Cloning, Molecular Cricetinae DNA Replication* Eukaryotic Initiation Factor-4E Fibroblast Growth Factors / genetics Gene Expression Regulation* / drug effects Hydroxyurea / pharmacology Microtubules / drug effects, ultrastructure Ornithine Decarboxylase / genetics Peptide Initiation Factors / genetics, metabolism* Polyribosomes / metabolism Protein Biosynthesis* RNA, Messenger / genetics Recombinant Proteins / metabolism Ribonucleotide Reductases / biosynthesis, genetics* S Phase Saccharomyces cerevisiae / genetics Transcription, Genetic* Transfection |
| Grant Support | |
ID/Acronym/Agency:
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CA69148/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Eukaryotic Initiation Factor-4E; 0/Peptide Initiation Factors; 0/RNA, Messenger; 0/Recombinant Proteins; 127-07-1/Hydroxyurea; 17804-35-2/Benomyl; 62031-54-3/Fibroblast Growth Factors; EC 1.17.4.-/Ribonucleotide Reductases; EC 4.1.1.17/Ornithine Decarboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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