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Blood, 15 July 2007, Vol. 110, No. 2, pp. 752-761. Prepublished online as a Blood First Edition Paper on April 11, 2007; DOI 10.1182/blood-2007-03-076737. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-03-076737v1 110/2/752    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fu, D. Articles by Richardson, D. R. Search for Related Content PubMed PubMed Citation Articles by Fu, D. Articles by Richardson, D. R. Related Collections Cell Cycle Gene Expression Free Research Articles Red Cells Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion Dong Fu1,2, and Des R. Richardson1,2 1 Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, and 2 Children's Cancer Institute Australia, Randwick, Sydney, Australia Iron (Fe) plays a critical role in proliferation, and Fe deficiency results in G1/S arrest and apoptosis. However, the precise role of Fe in cell-cycle control remains unclear. We observed that Fe depletion increased the mRNA of the universal cyclin-dependent kinase inhibitor, p21CIP1/WAF1, while its protein level was not elevated. This observation is unique to the G1/S arrest seen after Fe deprivation, as increased p21CIP1/WAF1 mRNA and protein are usually found when arrest is induced by other stimuli. In this study, we examined the posttranscriptional regulation of p21CIP1/WAF1 after Fe depletion and demonstrated that its down-regulation was due to 2 mechanisms: (1) inhibited translocation of p21CIP1/WAF1 mRNA from the nucleus to cytosolic translational machinery; and (2) induction of ubiquitin-independent proteasomal degradation. Iron chelation significantly (P < .01) decreased p21CIP1/WAF1 protein half-life from 61 (± 4 minutes; n = 3) to 28 (± 9 minutes, n = 3). Proteasomal inhibitors rescued the chelator-mediated decrease in p21CIP1/WAF1 protein, while lysosomotropic agents were not effective. In Fe-replete cells, p21CIP1/WAF1 was degraded in an ubiquitin-dependent manner, while after Fe depletion, ubiquitin-independent proteasomal degradation occurred. These results are important for considering the mechanism of Fe depletion–mediated cell-cycle arrest and apoptosis and the efficacy of chelators as antitumor agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Cell-cycle regulation by iron depletion Chaim Hershko Blood 2007 110: 474-475. [Full Text] [PDF] This article has been cited by other articles: T. Amit, Y. Avramovich-Tirosh, M. B. H. Youdim, and S. Mandel Targeting multiple Alzheimer's disease etiologies with multimodal neuroprotective and neurorestorative iron chelators FASEB J, May 1, 2008; 22(5): 1296 - 1305. [Abstract] [Full Text] [PDF]

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