| Regulation of p27(Kip1) by intracellular iron levels. | |
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MedLine Citation:
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PMID: 14977358 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Enhanced intracellular iron levels are essential for proliferation of mammalian cells. If cells have entered S phase when iron is limiting, an adequate supply of deoxynucleotides cannot be maintained and the cells arrest with incompletely replicated DNA. In contrast, proliferating cells that are not in S phase, but have low iron pools, arrest in late G1. In this report the mechanism of iron-dependent G1 arrest in normal fibroblasts was investigated. Cells were synchronized in G0 by contact inhibition and serum deprivation. Addition of serum caused the cells to re-enter the cell cycle and enter S phase. However, if the cells were also treated with the iron chelator deferoxamine, S phase entry was blocked. This corresponded to elevated levels of the cyclin dependent kinase inhibitor p27(Kip1) and inhibition of CDK2 activity. Expression of other cell cycle regulatory proteins was not affected, including the induction of cyclins D1 and E. When the quiescent serum starved cells were supplemented with a readily usable form of iron in the absence of serum or any other growth factors, a significant population of the cells entered S phase. This was associated with downregulation of p27(Kip1) and increased CDK2 activity. Using an IPTG-responsive construct to artificially raise p27(Kip1) levels blocked the ability of iron supplementation to promote S phase entry. Thus it appears that p27(Kip1) is a mediator of G1 arrest in iron depleted Swiss 3T3 fibroblasts. We propose that this is part of an iron-sensitive checkpoint that functions to ensure that cells have sufficient iron pools to support DNA synthesis prior to entry into S phase. |
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Authors:
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Gang Wang; Robin Miskimins; W Keith Miskimins |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine Volume: 17 ISSN: 0966-0844 ISO Abbreviation: Biometals Publication Date: 2004 Feb |
Date Detail:
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Created Date: 2004-02-23 Completed Date: 2004-09-03 Revised Date: 2012-06-25 |
Medline Journal Info:
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Nlm Unique ID: 9208478 Medline TA: Biometals Country: Netherlands |
Other Details:
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Languages: eng Pagination: 15-24 Citation Subset: IM |
Affiliation:
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University of South Dakota School of Medicine, Division of Basic Biomedical Sciences, Vermillion, SD 57069, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Animals CDC2-CDC28 Kinases / antagonists & inhibitors, metabolism Cell Cycle / drug effects Cell Cycle Proteins / genetics, metabolism* Cell Line Chelating Agents / pharmacology Cyclin D1 / metabolism Cyclin E / metabolism Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases / antagonists & inhibitors, metabolism Gene Expression Regulation Iron / metabolism* Mice Proto-Oncogene Proteins* Serum Tumor Suppressor Proteins / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA84325/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cdkn1b protein, mouse; 0/Cell Cycle Proteins; 0/Chelating Agents; 0/Cyclin E; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Proteins; 136601-57-5/Cyclin D1; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 7439-89-6/Iron; EC 2.7.11.22/CDC2-CDC28 Kinases; EC 2.7.11.22/Cdk2 protein, mouse; EC 2.7.11.22/Cdk4 protein, mouse; EC 2.7.11.22/Cyclin-Dependent Kinase 2; EC 2.7.11.22/Cyclin-Dependent Kinase 4; EC 2.7.11.22/Cyclin-Dependent Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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