Document Detail

Regulation of p27(Kip1) by intracellular iron levels.
MedLine Citation:
PMID:  14977358     Owner:  NLM     Status:  MEDLINE    
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.
Gang Wang; Robin Miskimins; W Keith Miskimins
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
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:
Created Date:  2004-02-23     Completed Date:  2004-09-03     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  9208478     Medline TA:  Biometals     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  15-24     Citation Subset:  IM    
University of South Dakota School of Medicine, Division of Basic Biomedical Sciences, Vermillion, SD 57069, USA.
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MeSH Terms
3T3 Cells
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*
Proto-Oncogene Proteins*
Tumor Suppressor Proteins / genetics,  metabolism*
Grant Support
Reg. No./Substance:
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 Kinases; EC protein, mouse; EC protein, mouse; EC Kinase 2; EC Kinase 4; EC Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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