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Blood, 1 May 2007, Vol. 109, No. 9, pp. 4045-4054.
Prepublished online as a Blood First Edition Paper on December 29, 2006; DOI 10.1182/blood-2006-10-047753.
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Submitted October 23, 2006
Accepted December 18, 2006
Iron Chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression
E Nurtjahja-Tjendraputra, D Fu, J M Phang, and D R Richardson*
Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, Australia
Iron Metabolism and Chelation Program, Children's Cancer Institute Australia for Medical Research, Sydney, Australia
* Corresponding author; email: d.richardson{at}med.usyd.edu.au.
Iron (Fe) plays an important role in proliferation and Fe-deficiency results in G1/S arrest. Despite this, the precise role of Fe in cell cycle control remains unclear. Cyclin D1 plays a critical function in G1 progression by interacting with cyclin-dependent kinases. Previously, we examined the effect of Fe-depletion on the expression of cell cycle control molecules and identified a marked decrease in cyclin D1 protein, although the mechanism involved was unknown (Gao J, Richardson DR Blood 2001;98:842-850). In this study, we showed that cyclin D1 was regulated post-transcriptionally by Fe-depletion. Iron chelation of cells in culture using desferrioxamine (DFO) or 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) decreased cyclin D1 protein levels after 14 h and was rescued by the addition of Fe. Cyclin D1 half-life in control cells was 80 ±; 15 min (n=5), while in chelator-treated cells it was significantly (p<0.008) decreased to 38 + 3 min (n=5). Proteasomal inhibitors rescued the Fe chelator-mediated decrease in cyclin D1 protein, suggesting the role of the proteasome. In Fe-replete cells, cyclin D1 was degraded in an ubiquitin-dependent manner, while Fe-depletion induced a ubiquitin-independent pathway. This is the first report linking Fe-depletion mediated growth suppression at G1/S to a mechanism inducing cyclin D1 proteolysis.
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