BACH1 is a specific repressor of HMOX1 that is inactivated by arsenite.
Intracellular heme is a redox active molecule that can be detrimental to cells at high concentrations or under oxidizing conditions. To prevent accumulation, the inducible enzyme heme oxygenase-1 (HMOX1) catalyzes degradation of heme. In the absence of elevated intracellular heme or oxidative stress, the basic region leucine zipper transcriptional regulator BACH1 binds HMOX1 antioxidant response elements and represses transcription. Conversely, increased intracellular heme or sulfhydryl oxidation inactivate BACH1, permitting transcriptional induction of HMOX1. Here, we investigate the effect of BACH1 inactivation on the induction of HMOX1 and as a mechanism for broader gene induction. We show that BACH1 is inactivated at low micromolar arsenite concentrations and that BACH1 inactivation is necessary and sufficient for transcriptional induction of HMOX1. Because BACH1 is thought to interact with antioxidant response element motifs, we further examined the role of BACH1 as a regulator of inducible antioxidant gene expression by assessing the global profile of gene expression following BACH1 knockdown using small interfering RNA. The loss of BACH1 function in human keratinocytes results almost exclusively in HMOX1 induction, suggesting that BACH1 may function as a rheostat regulating levels of intracellular free heme.
Reichard
John F
JF
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, Ohio 45267, USA. john.reichard@childrens.harvard.edu
Sartor
Maureen A
MA
Puga
Alvaro
A
D018053:Arsenites / Q000494:pharmacology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D017931:DNA Primers; D004790:Enzyme Induction; D051856:Fanconi Anemia Complementation Group Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D006418:Heme / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D016350:Leucine Zippers / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018053:Arsenites; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers; D051856:Fanconi Anemia Complementation Group Proteins; D012097:Repressor Proteins; D006418:Heme; D012313:RNA; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C015001:arsenite