Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression.
Iron (Fe) plays an important role in proliferation, and Fe deficiency results in G(1)/S arrest. Despite this, the precise role of Fe in cell-cycle control remains unclear. Cyclin D1 plays a critical function in G(1) 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. In this study, we showed that cyclin D1 was regulated posttranscriptionally 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 hours and was rescued by the addition of Fe. Cyclin D1 half-life in control cells was 80 +/- 15 minutes (n = 5), while in chelator-treated cells it was significantly (P < .008) decreased to 38 +/- 3 minutes (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 G(1)/S to a mechanism inducing cyclin D1 proteolysis.
Nurtjahja-Tjendraputra
Effie
E
Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, New South Wales 2006, Australia.
Fu
Dong
D
Phang
Juanita M
JM
Richardson
Des R
DR
D018798:Anemia, Iron-Deficiency / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects*; D017262:Siderophores / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
C120275:2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; D007502:Iron Chelating Agents; D017262:Siderophores; D025801:Ubiquitin; D007501:Iron; D046988:Proteasome Endopeptidase Complex; D003676:Deferoxamine; D007538:Isoniazid