Genetic regulation of cell function in response to iron overload or chelation.
Iron influences many aspects of cell function on different biochemical levels. This review considers effects mediated through iron-dependent changes in gene expression in mammalian cells. Several classes of related genes are responsive to cellular iron levels, but no clear patterns readily account for the toxicity of iron overload or the consequences of removal of iron with chelating agents. Here we group some of the genes influenced by iron status into those related to iron metabolism, oxygen and oxidative stress, energy metabolism, cell cycle regulation, and tissue fibrosis. Iron excess and chelation do not generally result in a continuous or graded transcriptional response, but indicate operation of distinct mechanisms. An emerging concept is that iron signals through generation of reactive oxygen species to activate transcription factors such as NF-kappaB, whereas iron removal mimics hypoxia, perhaps by disrupting iron-based O(2) sensors and influencing gene expression through, e.g., the hypoxia-inducible factor, HIF-1. Heme and other metalloporphyrins have other distinct mechanisms for regulating transcription. Regulation of gene expression through iron-responsive elements in mRNAs coded by several genes is one of the best understood mechanisms of translational control.
Templeton
Douglas M
DM
Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. doug.templeton@utoronto.ca
Liu
Ying
Y
D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004734:Energy Metabolism; D005293:Ferritins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology; D019190:Iron Overload / Q000503:physiopathology*; D033862:Iron-Binding Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D003676:Deferoxamine; D005293:Ferritins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D007502:Iron Chelating Agents; D033862:Iron-Binding Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D014157:Transcription Factors; D000099236:Solute Carrier Family 11, Member 2; C497442:HIF1A protein, human