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BTB and CNC homology 1, basic leucine zipper transcription factor 1
Heme oxygenase is the rate-limiting enzyme in heme catabolism that cleaves heme at the α-methene bridge to form biliverdin IXα, carbon monoxide, and iron. Biliverdin IXα is immediately converted to bilirubin IXα by biliverdin reductase that is transported to the liver for conjugation and excretion into bile. There are two heme oxygenase isozymes, heme oxygenase-1 (HO-1)1 and heme oxygenase-2 (HO-2). HO-1 is inducible and HO-2 is constitutively expressed in human cells. HO-1 catalyzes heme breakdown, eventually releasing iron, carbon monoxide, and bilirubin IX. HO-1 is induced by its substrate heme and various environmental factors, which represents a protective response against oxidative stresses. The inducible enhancers of the HO-1 gene (referred to as E1 and E2) carry multiple Maf recognition elements (MARE). NF-E2-related factor 2 (Nrf2), which belongs to the basic leucin zipper (bZip) family of transcriptional factors, binds to MARE to form a heterodimer with Maf family protein, leading to activation of the HO-1 gene expression.
On the other hand, binding of Bach1, another bZip transcriptional factor identified by Igarashi and coworker, binds to MARE to form a heterodimer with a Maf family protein as does Nrf2, leading to repression of HO-1 gene expression. However, the ability of Nrf2 to stimulate HO-1 expression is greatly reduced in the presence of Bach1, suggesting that the activity of Bach1 to suppress HO-1 expression is dominant over the activity of HO-1 inducers, including Nrf2, and when exposed to deferoxamine, an interferon-γ or iron chelator, HO-1 expression is also reduced in human cells, each of which induced Bach1 expression. In contrast, induction of HO-1 expression by CoCl2 is associated with reduced expression of Bach1 mRNA. Thus, the expression of HO-1 and Bach1 is inversely regulated.
Recently, Sun et al. has been shown that HO-1 is expressed constitutively at higher levels in many tissues of bach1-deficient mice, indicating that Bach1 acts as a negative regulator of transcription of the mouse HO-1 gene. In fact, the Bach1-MafK heterodimer binds to the MAREs of the HO-1 gene enhancers, thereby repressing transcription. Importantly, Bach1-heme interaction plays a pivotal role in the mechanism of stress-inducible HO-1 upregulation. Heme has strong affinity to Bach1. Upon binding with heme, Bach1 loses its DNA binding activity and is exported out of the nucleus, which causes MARE to be accessible for many HO-1 inducers, including Nrf2, to stimulate HO-1 expression unlimitedly. Thus, heme- or oxidative stress-mediated de-repression is the central mechanism of HO-1 upregulation. Oxidative stressors such as Cd also induce the nuclear export of Bach1. Bach1, in its molecule, contains sequences that are sensitive to both free heme and oxidative stressor such as Cd, deletion of which leads to loss of the stress-induced upregulation of HO-1, indicating that Bach1 directly senses the oxidative stress at least in part through the intracellular free heme concentration. Although the role of heme (free-heme) as a central mediator of oxidative stress has not been completely elucidated, it is plausible that the intracellular heme level increases upon oxidative stress because there are many heme proteins (e.g. cytochrome, NO synthase, cyclooxygenase) in cells and heme apoprotein binding may become unstable in stress-injured conditions. Thus, in this heme-mediated antioxidant defense mechanism, Bach1 plays a pivotal role to sense the oxidative stress directly and translate the input out into upregulation of cytoprotective HO-1 expression. (Fig 1).
Fig 1. Regulation of HO-1 gene expression through heme-Bach1 interaction. (R. Ozono. Current Pharmaceutical Biotechnology, 2006.).
In addition, BACH1 has been widely expressed in human tissues. Reduced expression of HO-1 mRNA in human cells by the treatment with hypoxia, desferrioxamine, or interferon-γ, each of which consistently induces Bach1 Mrna expression. In addition, expression levels of Bach1 mRNA are decreased by the treatment with CoCl2 that remarkably induces HO-1 expression. Thus, there is an inverse relationship between the level of expression between HO-1 and Bach1. These results indicate that Bach1 may act as a metabolic sensor. Importantly, the study has identified Bach1 as a hypoxia-inducible regulator that represses the transcription of the HO-1 gene in human cells; Bach1 represents an integral part of the hypoxia-induced repressor because Bach1 functions as heterodimers with one of small Maf proteins. Under hypoxic conditions, HIF-1, a key regulator in hypoxic response, is functionally activated in A549 human lung cancer cells as well as in T98G glioblastoma cells and HUVECs. Human cells therefore fine-tune oxygen homeostasis by inducing Bach1 and HIF-1 in response to hypoxia.