Bach1 Functions as a Hypoxia-inducible Repressor for the Heme Oxygenase-1 Gene in Human Cells

Abstract

Heme oxygenase (EC 1.14.99.3) is the rate-limiting enzyme in heme catabolism that cleaves heme at the ␣-methene bridge to form biliverdin IX␣, carbon monoxide, and iron (1, 2). Biliverdin IX␣ is immediately converted by biliverdin reductase to bilirubin IX␣ that is transported to the liver for conjugation and excretion into bile (3). There are two isozymes of heme oxygenase, heme oxygenase-1 (HO-1) 1 and heme oxygenase-2 (HO-2) (4, 5). HO-1 is inducible whereas HO-2 is constitutively expressed in human cells (6). Expression of HO-1 mRNA is highly increased in human cells by the substrate heme (7), heavy metals (8, 9), UV irradiation (10), and nitric oxide donors (11)(12)(13)(14). Because bilirubin IX␣ functions as a natural radical scavenger (15, 16), induction of HO-1 probably represents a protective response against oxidative stress. The physiological importance of HO-1 has been confirmed by the phenotypic consequences of the HO-1-deficient mice (17) and a patient with HO-1 deficiency (18).Induction of HO-1 has been extensively studied for the last few decades by many investigators. In contrast, repression of HO-1 expression has been largely ignored, despite its physiological importance (3). We have shown that HO-1 is not induced or rather reduced by heat shock in human cells (19), whereas rat HO-1 is a heat shock protein (20,21). The expression levels of HO-1 are also decreased in human glioblastoma cells by the treatment with interferon-␥ (22). In addition, hypoxia represses HO-1 mRNA expression in primary cultures of human umbilical vein endothelial cells (HUVECs), human astrocytes, and human coronary arterial endothelial cells (23). On the other hand, hypoxia increased HO-1 expression in rat liver (24) and heart (25) and in various cultured animal cells, including Chinese hamster ovary cells (26), rat ventricular smooth muscle cells (27,28), and rat myocytes (29). These results suggest the inter-species difference in the regulation of HO-1 gene expression by hypoxia between human and animal cells.The inter-species variations in the hypoxic response are of clinical significance because hypoxia is involved in the pathophysiology of various disorders, including ischemic heart disease, cerebrovascular disease, cancer, sleep apnea syndrome, and chronic obstructive pulmonary disease, which account for common causes of death and disability in the developed world. Mammalian cells respond to hypoxia in part by increased expression of several genes coding for erythropoietin (30), vascular endothelial growth factor (31), adrenomedullin (32, 33), and glycolytic enzymes (34,35), all of which cooperate to protect cells and tissues against the hypoxic state. Hypoxia-inducible

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

“…Bach1, a basic leucine zipper protein, is a heme-regulated transcriptional repressor found in mammals [72,73]. The activity of Bach1 is modulated by heme [72,73].…”

“…The activity of Bach1 is modulated by heme [72,73]. Bach1 forms heterodimers with proteins in the Maf-related oncoprotein family (MafK, MafF, MafG) ( Figure 1, Table 1).…”

“…Bach1 forms heterodimers with proteins in the Maf-related oncoprotein family (MafK, MafF, MafG) ( Figure 1, Table 1). The Bach1-Maf heterodimers bind to the Maf recognition element (MARE) in the regulatory region of its target genes [72,[74][75][76][77]. MAREs are found in the regulatory regions of genes involved in heme metabolism, such as oxidative stress response genes, globin genes, heme oxygenase-1 and erythroid-specific ALAS [72,[78][79][80][81].…”

“…The regulation of HO-1 expression by these factors is not only cell type-dependent but also species-dependent [162,164]. For example, hypoxia induces HO-1 expression in rodent, bovine and monkey cells, but represses HO-1 expression in several human cell lines, including lung cancer A549 cells, umbilical vein endothelial cells and glioblastoma cells [72,[165][166][167][168][169][170]. A detailed discussion of HO-1 regulation can be found in an excellent review written by Sikorki et al [162].…”

The role and clinical implications of microRNAs in hepatocellular carcinoma

“…Moreover, miR-196 is able to repress oxidative damage by targeting the transcription regulator protein Bach1 [48]. Bach1 is a well-established repressor of the heme oxygenase 1 (HMOX1) gene [49,50], a major cytoprotective enzyme with antioxidant and anti-inflammatory activities [51][52][53]. miR-196 induction downregulates Bach1 and upregulates HMOX1 in human hepatoma 9-13 cells [54].…”