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National Institute of Environmental Health Sciences

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Publication Detail

Title: Hemin-mediated regulation of an antioxidant-responsive element of the human ferritin H gene and role of Ref-1 during erythroid differentiation of K562 cells.

Authors: Iwasaki, Kenta; Mackenzie, Elizabeth L; Hailemariam, Kiros; Sakamoto, Kensuke; Tsuji, Yoshiaki

Published In Mol Cell Biol, (2006 Apr)

Abstract: An effective utilization of intracellular iron is a prerequisite for erythroid differentiation and hemoglobinization. Ferritin, consisting of 24 subunits of H and L, plays a crucial role in iron homeostasis. Here, we have found that the H subunit of the ferritin gene is activated at the transcriptional level during hemin-induced differentiation of K562 human erythroleukemic cells. Transfection of various 5' regions of the human ferritin H gene fused to a luciferase reporter into K562 cells demonstrated that hemin activates ferritin H transcription through an antioxidant-responsive element (ARE) that is responsible for induction of a battery of phase II detoxification genes by oxidative stress. Gel retardation and chromatin immunoprecipitation assays demonstrated that hemin induced binding of cJun, JunD, FosB, and Nrf2 b-zip transcription factors to AP1 motifs of the ferritin H ARE, despite no significant change in expression levels or nuclear localization of these transcription factors. A Gal4-luciferase reporter assay did not show activation of these b-zip transcription factors after hemin treatment; however, redox factor 1 (Ref-1), which increases DNA binding of Jun/Fos family members via reduction of a conserved cysteine in their DNA binding domains, showed induced nuclear translocation after hemin treatment in K562 cells. Consistently, Ref-1 enhanced Nrf2 binding to the ARE and ferritin H transcription. Hemin also activated ARE sequences of other phase II genes, such as GSTpi and NQO1. Collectively, these results suggest that hemin activates the transcription of the ferritin H gene during K562 erythroid differentiation by Ref-1-mediated activation of these b-zip transcription factors to the ARE.

PubMed ID: 16537925 Exiting the NIEHS site

MeSH Terms: Antioxidants/metabolism; Antioxidants/pharmacology*; Basic-Leucine Zipper Transcription Factors/metabolism; Cell Differentiation*; Cells, Cultured; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism*; Erythroid Cells/cytology*; Ferritins/genetics*; Gene Expression Regulation/drug effects; Gene Expression Regulation/genetics; Glutathione S-Transferase pi/metabolism; Hemin/pharmacology*; Humans; K562 Cells; NAD(P)H Dehydrogenase (Quinone)/metabolism; Protein Binding; RNA, Messenger/genetics; RNA, Messenger/metabolism; Response Elements/genetics*; Transcriptional Activation/genetics

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