Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells.
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.
Kitamuro
Tomomi
T
Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai 980-8575, Japan.
Takahashi
Kazuhiro
K
Ogawa
Kazuhiro
K
Udono-Fujimori
Reiko
R
Takeda
Kazuhisa
K
Furuyama
Kazumichi
K
Nakayama
Masaharu
M
Sun
Jiying
J
Fujita
Hiroyoshi
H
Hida
Wataru
W
Hattori
Toshio
T
Shirato
Kunio
K
Igarashi
Kazuhiko
K
Shibahara
Shigeki
S
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D015152:Blotting, Northern; D015153:Blotting, Western; D002417:Cattle; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D019281:Dimerization; D051856:Fanconi Anemia Complementation Group Proteins; D005786:Gene Expression Regulation; D006418:Heme / Q000737:chemistry; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D000860:Hypoxia; D007371:Interferon-gamma / Q000494:pharmacology; D016350:Leucine Zippers; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins; D008957:Models, Genetic; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D003609:Dactinomycin; D003035:Cobalt; D006418:Heme; D007371:Interferon-gamma; D008156:Luciferases; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C018021:cobaltous chloride; D003676:Deferoxamine; D010100:Oxygen