Biliverdin reductase (BVR) is an evolutionary conserved protein, with an unmatched range of cellular functions. BVR is expressed to a varying degree in all tissues, the liver parenchyma cells are the primary site of its activity. As a reductase, it converts biliverdin which is a hepatotoxin and inhibitor of kinases and NF-:B, to the potent antioxidant, bilirubin. Biliverdin is a modulator of liver tumor cell growth, AhR ligand, and is elevated in carriers of BVR mutation with end-stage liver cirrhosis. Indeed, a compromised BVR activity causes "green jaundice", which is nearly always fatal. We have shown, in addition to its reductase activity, BVR is a Ser/Thr/Tyr kinase, a cellular scaffold/bridge for MEK/ERK/Elk activation, a nuclear transporter of ERK1/2 and hematin, a leucine-zipper (bZip) transcription factor, a regulator of TNF-1- activated kinase-mediator of autoimmunity and activator of NF-:B. Demonstrated functions of BVR include regulation and/or activation of kinases in the insulin/IGF/MAPK/PI3K signaling pathways that regulate glucose uptake, cell growth, apoptosis and stress-response gene expression (c-fos, c-jun, HO-1, CREB/ATF- 2). The human (h)BVR is regulated by IGF-1 and is an activator of the signaling pathway downstream of the growth factor. The discovery that small BVR-based peptides can effectively intervene in the MAPK pathway at several key junctions is a highly relevant finding toward the development of novel therapeutic agents. Furthermore, transformed cells stably transfected with hBVR display a most striking differentiated morphology and growth in size. Gene array analysis suggested increases in EGFR and hBVR are linked;EGF is the regulator of STAT/JAK signaling. Notably, the hBVR promoter contains consensus sequences for binding STAT1 and Elk;and, in a yeast two-hybrid screening of high stringency, JAK2 kinase was identified as hBVR binding partner;hBVR, STAT1 and Elk are activated by cytokines. Presently, we hypothesize that BVR functions in defining cytoskeletal organization and regulation of cell cycle progression events that are mediated by growth factors. We further hypothesize that disruption of hBVR activity will protect liver damage induced by cytokines. To test these hypotheses:
Specific Aim 1 will investigate hBVR function in cell signaling pathways that control cell growth/proliferation, differentiation and mobility in HepG2 cells stimulated by EGF.
Specific Aim 2 will characterize hBVR promoter with focus on the potential regulatory loops with STAT1 and Elk.
Specific Aim 3 will evaluate in primary rat hepatocytes and in ex vivo perfused rat liver protection by hBVR peptides against interferon-3-mediated toxicity. Impact: BVR is poised to occupy a key role in regulation of a wide range of cellular functions;therefore, BVR-based technology is a viable target for development of novel therapeutic approaches. We believe the outlined investigations most likely will stimulate new directions of investigation in the development of therapeutic targets that will have positive impact on public health. Findings with hBVR-peptides underscore the plausibility of this perception.

Public Health Relevance

There are key juncture in the pathways that govern adaptive and protective regulatory mechanisms of the cell by relaying signals initiated at the cell membrane to the nucleus of the cell for generating appropriate response. Therefore, control of their activity is vital to maintenance of cellular integrity. In the recent years, we have discovered that the enzyme, biliverdin reductase, controls function of all key steps examined to date in the pathways that regulate response of the cell to insulin/insulin-like growth factor, oxidative stress and inflammatory agents. In addition, the enzyme activity is necessary for protection against the fatal green jaundice. Our work has revealed a novel approach for development of therapeutic interventions in a range of human diseases.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Shreffler, Carol K
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University of Rochester
Schools of Dentistry
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Gibbs, Peter E M; Lerner-Marmarosh, Nicole; Poulin, Amelia et al. (2014) Human biliverdin reductase-based peptides activate and inhibit glucose uptake through direct interaction with the kinase domain of insulin receptor. FASEB J 28:2478-91
Gibbs, Peter E M; Miralem, Tihomir; Lerner-Marmarosh, Nicole et al. (2012) Formation of ternary complex of human biliverdin reductase-protein kinase C?-ERK2 protein is essential for ERK2-mediated activation of Elk1 protein, nuclear factor-?B, and inducible nitric-oxidase synthase (iNOS). J Biol Chem 287:1066-79
Ding, Bo; Gibbs, Peter E M; Brookes, Paul S et al. (2011) The coordinated increased expression of biliverdin reductase and heme oxygenase-2 promotes cardiomyocyte survival: a reductase-based peptide counters *-adrenergic receptor ligand-mediated cardiac dysfunction. FASEB J 25:301-13
Maines, Mahin D (2010) Potential application of biliverdin reductase and its fragments to modulate insulin/IGF-1/MAPK/PI3-K signaling pathways in therapeutic settings. Curr Drug Targets 11:1586-94
Miralem, Tihomir; Gibbs, Peter E M; Revert, Fernando et al. (2010) Human biliverdin reductase suppresses Goodpasture antigen-binding protein (GPBP) kinase activity: the reductase regulates tumor necrosis factor-alpha-NF-kappaB-dependent GPBP expression. J Biol Chem 285:12551-8
Kapitulnik, Jaime; Maines, Mahin D (2009) Pleiotropic functions of biliverdin reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin. Trends Pharmacol Sci 30:129-37
Lerner-Marmarosh, Nicole; Miralem, Tihomir; Gibbs, Peter E M et al. (2008) Human biliverdin reductase is an ERK activator;hBVR is an ERK nuclear transporter and is required for MAPK signaling. Proc Natl Acad Sci U S A 105:6870-5
Tudor, Cicerone; Lerner-Marmarosh, Nicole; Engelborghs, Yves et al. (2008) Biliverdin reductase is a transporter of haem into the nucleus and is essential for regulation of HO-1 gene expression by haematin. Biochem J 413:405-16
Lerner-Marmarosh, Nicole; Miralem, Tihomir; Gibbs, Peter E M et al. (2007) Regulation of TNF-alpha-activated PKC-zeta signaling by the human biliverdin reductase: identification of activating and inhibitory domains of the reductase. FASEB J 21:3949-62
Maines, Mahin D; Miralem, Tihomir; Lerner-Marmarosh, Nicole et al. (2007) Human biliverdin reductase, a previously unknown activator of protein kinase C betaII. J Biol Chem 282:8110-22

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