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Molecular and Cellular Biology, April 2006, p. 2845-2856, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2845-2856.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Kenta Iwasaki,1,{dagger} Elizabeth L. MacKenzie,1,{dagger} Kiros Hailemariam,1 Kensuke Sakamoto,1,2 and Yoshiaki Tsuji1*

Department of Environmental and Molecular Toxicology, North Carolina State University, Campus Box 7633, Raleigh, North Carolina 27695,1 Graduate School of Systems Life Science, Kyushu University, Fukuoka 812-8581, Japan2

Received 8 September 2005/ Returned for modification 21 October 2005/ Accepted 11 January 2006

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.

* Corresponding author. Mailing address: North Carolina State University, Campus Box 7633, Raleigh, NC 27695. Phone: (919) 513-1106. Fax: (919) 515-7169. E-mail: yoshiaki_tsuji{at}ncsu.edu.

{dagger} The first two authors contributed equally to this work.

Molecular and Cellular Biology, April 2006, p. 2845-2856, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2845-2856.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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