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

J Biol Chem. 2003 Mar 14;278(11):9125-33. doi: 10.1074/jbc.M209939200. Epub 2003 Jan 2.

Abstract

Heme oxygenase 1 (HO-1) catalyzes heme breakdown, eventually releasing iron, carbon monoxide, and bilirubin IXalpha. 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-gamma or an iron chelator desferrioxamine, each of which induced Bach1 expression. In contrast, induction of HO-1 expression by CoCl(2) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors
  • Blotting, Northern
  • Blotting, Western
  • Cattle
  • Cell Line
  • Cobalt / pharmacology
  • Dactinomycin / pharmacology
  • Deferoxamine / pharmacology
  • Dimerization
  • Fanconi Anemia Complementation Group Proteins
  • Gene Expression Regulation
  • Heme / chemistry
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Heme Oxygenase-1
  • Humans
  • Hypoxia*
  • Interferon-gamma / pharmacology
  • Leucine Zippers
  • Luciferases / metabolism
  • Membrane Proteins
  • Models, Genetic
  • Oxidative Stress
  • Oxygen / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Rats
  • Time Factors
  • Transcription Factors / metabolism*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Fanconi Anemia Complementation Group Proteins
  • Membrane Proteins
  • RNA, Messenger
  • Transcription Factors
  • Dactinomycin
  • Cobalt
  • Heme
  • Interferon-gamma
  • Luciferases
  • HMOX1 protein, human
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • cobaltous chloride
  • Deferoxamine
  • Oxygen