Characterization of the human biliverdin reductase gene structure and regulatory elements: Promoter activity is enhanced by hypoxia and suppressed by TNF-α-activated NF-κB
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA. The FASEB Journal
(Impact Factor: 5.04).
09/2010; 24(9):3239-54. DOI: 10.1096/fj.09-144592
hBVR is a Ser/Thr/Tyr kinase/scaffold protein/transcription factor/intracellular transporter of regulators. hBVR is an upstream activator of the insulin/IGF-1/MAPK/PI3K signaling pathway, and of NF-kappaB. As a reductase, it converts biliverdin to the antioxidant, bilirubin. hBVR gene has 8 exons; exon 1 is not translated. We report the characterization of hBVR promoter and its negative and positive regulation, respectively, by TNF-alpha and hypoxia. The 5' end of exon 1 was defined by primer extension analyses; deletion of an inhibitor sequence 350-425 bp upstream of this exon enhanced the promoter activity. One of two NF-kappaB binding sites in the 836-bp promoter was functional; the P65 subunit of NF-kappaB and TNF-alpha acted as inhibitors. On the basis of EMSA and ChIP assays, TNF-alpha treatment increases binding of NF-kappaB to its regulatory element. Overexpression of IkappaB increased hBVR mRNA. Biliverdin, but not bilirubin, was as effective as TNF-alpha in inhibiting hBVR promoter activity. Only one of 4 hypoxia responsive elements (HREs) bound to HIF-1alpha and ARNT expressed in HEK293A cells. An abasic site was introduced at the 3' G of the HRE. This element bound HIF-1 in the gel shift and in in-cell luciferase assays. hBVR was detected in the nucleus at 1, 2, and 4 h after hypoxia (1% O(2)), at which times its kinase and reductase activities were increased. Because hypoxia positively influences hBVR promoter and phosphorylation and TNF-alpha activated NF-kappaB inhibits the promoter, while biliverdin inhibits both NF-kappaB activity and hBVR promoter, we propose a regulatory mechanism for NF-kappaB by hypoxia and TNF-alpha centered on hBVR/biliverdin.
Available from: Zhaowen Zhu
- "Primary induction of interferon by BV in vitro has not been reported previously and appears contrary to the known anti-inflammatory character of BV and HO-1 induction. BV has been shown to induce nuclear accumulation of biliverdin reductase which then decreases nuclear NFkB in Hek293 cells (Gibbs and Maines, 2007; Gibbs et al., 2010). The latter findings are consistent with an immunosuppressive role for BV (Ollinger et al., 2007) in contrast to the more pro-inflammatory properties of heme (Gozzelino et al., 2010). "
[Show abstract] [Hide abstract]
ABSTRACT: Hepatitis C virus, human immunodeficiency virus, and hepatitis B virus are chronic viral infections that cause considerable morbidity and mortality throughout the world. In the decades following the identification and sequencing of these viruses, in vitro experiments demonstrated that heme oxygenase-1, its oxidative products, and related compounds of the heme oxygenase system inhibit replication of all 3 viruses. The purpose of this review is to critically evaluate and summarize the seminal studies that described and characterized this remarkable behavior. It will also discuss more recent work that discovered the antiviral mechanisms and target sites of these unique antiviral agents. In spite of the fact that these viruses are diverse pathogens with quite profound differences in structure and life cycle, it is significant that heme and related compounds show striking similarity for viral target sites across all three species. Collectively, these findings strongly indicate that we should move forward and develop heme and related tetrapyrroles into versatile antiviral agents that could be used therapeutically in patients with single or multiple viral infections.
Available from: Leo E Otterbein
- "Regulation of HO-1 and BVR expression and their enzymatic activity is critical for function of the heme degradation pathway. BVR expression is regulated negatively by NF-κB activation and positively by hypoxia-mediated HIF1α stabilization and specific HRE binding sites in the BVR promoter (Gibbs et al., 2010). BVR is strongly induced by its substrate , biliverdin as well as other agents that induce oxidative stress including LPS, heavy metals, and toxins (Maines et al., 2001; Wegiel et al., 2009). "
[Show abstract] [Hide abstract]
ABSTRACT: Biliverdin (BV) has emerged as a cytoprotective and important anti-inflammatory molecule. Conversion of BV to bilirubin (BR) is catalyzed by biliverdin reductase (BVR) and is required for the downstream signaling and nuclear localization of BVR. Recent data by others and us make clear that BVR is a critical regulator of innate immune responses resulting from acute insult and injury and moreover, that a lack of BVR results in an enhanced proinflammatory phenotype. In macrophages, BVR is regulated by its substrate BV which leads to activation of the PI3K-Akt-IL-10 axis and inhibition of TLR4 expression via direct binding of BVR to the TLR4 promoter. In this review, we will summarize recent findings on the role of BVR and the bile pigments in inflammation in context with its activity as an enzyme, receptor, and transcriptional regulator.
Available from: James Robert Reed
- "In addition to activating NFκB, BVR also binds to the transcription factor in a manner that modulates its activity to favor protective gene expression relative to harmful pro-apoptotic, pro-inflammatory and pro-proliferative targets (Gibbs et al., 2010). Consistent with the possibility that BVR regulates the activity of NFκB, TNF-α-mediated stimulation caused NFκB to act as a repressor of BVR expression which demonstrates that BVR is competitive with the inflammation process mediated by TNF-α through activation of NFκB. "
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.