The heme moiety of denatured hemoproteins (heme-proteins) is degraded by HO-1 &HO-2, to CO and biliverdin (BV), an HO activity inhibitor;BV is reduced by its reductase (BVR) to the antioxidant, bilirubin. CO has anti-inflammatory and vasodilatory activities. Stimuli that cause oxidative stress and hemoprotein denaturation, such as surgical interventions, inherited and transmitted hemolytic diseases, and certain drugs, industrial and environmental agents, induce ho-1. The kidney tubules are the target of potent pro-oxidant activity of heme-compounds. To date, no effective strategy has been described to counter heme-protein renal toxicity;however, increase in HO-1 activity by activation of stress-activated response elements, e.g., AP-1/CRE, AREs (antioxidant response elements) is considered cytoprotective. The activation involves cell-line independent binding of basic leucine zipper (bZip) transcription factors: c-Jun, ATF- 2/CREB, and Nrf2. The MAPK and PI3-K pathways transduce signals for activation of bZip factors and """"""""cross talk"""""""" using PKCs. bZip factor activity is subject to the identity of its dimeric partner. Phosphorylation of the ultimate target gene product, e.g., HO-1, alters its activity and turnover. In vitro and in cultured cells, we have discovered that: the human (h) BVR is one of the rare kinases that control MAPK and PI3-K signaling;is a bZip factor;activated by ho-1 inducers;and, traffics between the cytosol and nucleus. hBVR binds to AP-l/CRE and ARE elements and also enhances ATF-2 and Nrf2 binding to AP-1 and/or ARE;promotes induction and activation of ATF-2, c-Jun and c-Fos;activates kinase mediators of ho-1 response, i.e. PKCs and PKB/Akt;and, causes cell differentiation. BVR regulates ho-1 oxidative stress response and its anti-apoptotic effect. The overall objective of this application is to further investigate regulation of HO-1 activity by BVR at the molecular and cellular levels and to extend the investigation to the intact animal.
Specific aims are to examine: i) function of BVR as kinase:kinase in phosphorylation, activity, and turnover of HO-1;2) the role of hBVR in transcriptional activity of ATF-2 and Nrf2;and, 3) whether increased levels of BVR protect against heme-mediated injury. Mice expressing hBVR in renal tubules and treated with the hemolytic agent, phenylhydrazine, will be analyzed for pathophysiology, antioxidant status, kinase activities and HO-1 levels. Liver will serve as the non-target organ as control for the expression of the transgene.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012187-07
Application #
7650440
Study Section
Special Emphasis Panel (ZRG1-DIG-F (02))
Program Officer
Balshaw, David M
Project Start
2003-07-15
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
7
Fiscal Year
2009
Total Cost
$340,188
Indirect Cost
Name
University of Rochester
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Gibbs, Peter E M; Tudor, Cicerone; Maines, Mahin D (2012) Biliverdin reductase: more than a namesake - the reductase, its Peptide fragments, and biliverdin regulate activity of the three classes of protein kinase C. Front Pharmacol 3:31
Miralem, Tihomir; Lerner-Marmarosh, Nicole; Gibbs, Peter E M et al. (2012) The human biliverdin reductase-based peptide fragments and biliverdin regulate protein kinase C? activity: the peptides are inhibitors or substrate for the protein kinase C. J Biol Chem 287:24698-712
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
Gibbs, Peter E M; Miralem, Tihomir; Maines, Mahin D (2010) Characterization of the human biliverdin reductase gene structure and regulatory elements: promoter activity is enhanced by hypoxia and suppressed by TNF-alpha-activated NF-kappaB. FASEB J 24:3239-54
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

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