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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.
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 depletion1 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 depletionmediated cell-cycle arrest and apoptosis and the efficacy of chelators as antitumor agents.
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