Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells

Tomomi Kitamuro, Kazuhiro Takahashi, Kazuhiro Ogawa, Reiko Udono-Fujimori, Kazuhisa Takeda, Kazumichi Furuyama, Masaharu Nakayama, Jiying Sun, Hiroyoshi Fujita, Wataru Hida, Toshio Hattori, Kunio Shirato, Kazuhiko Igarashi, Shigeki Shibahara

Research output: Contribution to journalArticlepeer-review

203 Citations (Scopus)

Abstract

Heme oxygenase 1 (HO-1) catalyzes heme breakdown, eventually releasing iron, carbon monoxide, and bilirubin IXα. HO-1 is induced by its substrate heme and various environmental factors, which represents a protective response against oxidative stresses. Here we show that hypoxia represses HO-1 expression in three human cell types but induces it in rat, bovine, and monkey cells, indicating the inter-species difference in the hypoxic regulation of HO-1 expression. The hypoxia-mediated repression of HO-1 expression is consistently associated with the induction of Bach1, a heme-regulated transcriptional repressor, in human cells. Bach1 is a basic leucine zipper protein, forming a heterodimer with a small Maf protein. Expression of HO-1 was also reduced in human cells when exposed to interferon-α or an iron chelator desferrioxamine, each of which induced Bach1 expression. In contrast, induction of HO-1 expression by CoCl2 is associated with reduced expression of Bach1 mRNA. Thus, expression of HO-1 and Bach1 is inversely regulated. We have identified a Maf recognition element in the human HO-1 gene that is required for repression of a reporter gene by hypoxia and targeted by Bach1. Therefore, Bach1 functions as a hypoxia-inducible repressor for the HO-1 gene, thereby contributing to fine-tuning of oxygen homeostasis in human cells.

Original languageEnglish
Pages (from-to)9125-9133
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number11
DOIs
Publication statusPublished - 2003 Mar 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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