| Counteraction of pRb-dependent protection after extreme hypoxia by elevated ribonucleotide reductase. | |
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MedLine Citation:
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PMID: 15377335 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have studied hypoxia-induced cell cycle arrest in human cells where the retinoblastoma tumour suppressor protein (pRb) is either functional (T-47D and T-47DHU-res cells) or abrogated by expression of the HPV18 E7 oncoprotein (NHIK 3025 cells). We have previously found that pRb is dephosphorylated and rebound in the nucleus in T-47D cells arrested in S-phase during hypoxia and that this binding is protracted even following re-oxygenation. In the present study, however, we show that the long-lasting arrest following re-oxygenation induced by pRb-binding in the cell nuclei may be overruled by an elevated level of ribonucleotide reductase (RNR). This seems to create a forced DNA-synthesis, uncoordinated with cell division, which induces endoreduplication of the DNA. The data indicate that the cells initiating endoreduplication continue DNA-synthesis until all DNA is replicated once and then may start cycling and cell division with a doubled DNA-content. Corresponding data on the pRb-incompetent NHIK 3025-cells show similar endoreduplication in these. Thus, the data indicate that endoreduplication of DNA following re-oxygenation may come, either as a result of hypoxic arrest of DNA-synthesis when pRb-function is absent in the cells, or if it is overruled by increased RNR. The present study further shows that pRb not only protects the culture by arresting most of the cells that are exposed to extreme hypoxia in S-phase, but also increases cell survival by means of increased clonogenic ability of these cells. Interestingly, however, cells having an elevated level of RNR have equally high survival as wild-type cells following 20 h extreme hypoxia. If RNR-overruling of pRb-mediated arrest following re-oxygenation results in an unstable genome, this may therefore represent a danger of oncogenic selection as the protective effect of pRb on cell survival seems to be maintained. |
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Authors:
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P Graff; J Seim; Ø Amellem; H Arakawa; Y Nakamura; K K Andersson; T Stokke; E O Pettersen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cell proliferation Volume: 37 ISSN: 0960-7722 ISO Abbreviation: Cell Prolif. Publication Date: 2004 Oct |
Date Detail:
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Created Date: 2004-09-20 Completed Date: 2004-10-27 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9105195 Medline TA: Cell Prolif Country: England |
Other Details:
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Languages: eng Pagination: 367-83 Citation Subset: IM |
Affiliation:
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Department of Physics, The Biophysics Group, The University of Oslo, Oslo, Norway. pal.graff@fys.uio.no |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Cycle
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genetics* Cell Cycle Proteins / genetics, metabolism Cell Division / genetics Cell Hypoxia / genetics Cell Line, Tumor Cell Survival / genetics Cell Transformation, Neoplastic / genetics DNA Replication / genetics Humans Oncogenes / genetics Oxygen / metabolism Protein Binding / genetics Retinoblastoma Protein / genetics, metabolism* Ribonucleotide Reductases / metabolism* S Phase / genetics Tumor Stem Cell Assay Up-Regulation / genetics* |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/Retinoblastoma Protein; 7782-44-7/Oxygen; EC 1.17.4.-/Ribonucleotide Reductases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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