Human Biliverdin Reductase Is a Leucine Zipper-like DNA-binding Protein and Functions in Transcriptional Activation of Heme Oxygenase-1 by Oxidative Stress

Ahmad, Zulfiqar; Salim, Mohammad; Maines, Mahin D.

doi:10.1074/jbc.m108239200

Cited by 93 publications

(98 citation statements)

References 49 publications

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“…It has been shown by others that BVR can function as a kinase (3,4) and as a transcription factor involved in the regulation of heme oxygenase-1 (5). BVR is present in various compartments of the cell including the inner cell membrane in endothelial cells in association with HO-1 (18,19).…”

Section: Discussionmentioning

confidence: 99%

Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt

Węgiel

Baty

Gallo

et al. 2009

Journal of Biological Chemistry

138

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Biliverdin reductase A (BVR) catalyzes the reduction of biliverdin (BV) to bilirubin (BR) in all cells. Others and we haveshown that biliverdin is a potent anti-inflammatory molecule, however, the mechanism by which BV exerts its protective effects is unclear. We describe and elucidate a novel finding demonstrating that BVR is expressed on the external plasma membrane of macrophages (and other cells) where it quickly converts BV to BR. The enzymatic conversion of BV to BR on the surface by BVR initiates a signaling cascade through tyrosine phosphorylation of BVR on the cytoplasmic tail. Phosphorylated BVR in turn binds to the p85␣ subunit of phosphatidylinositol 3-kinase and activates downstream signaling to Akt. Using bacterial endotoxin (lipopolysaccharide) to initiate an inflammatory response in macrophages, we find a rapid increase in BVR surface expression. One of the mechanisms by which BV mediates its protective effects in response to lipopolysaccharide is through enhanced production of interleukin-10 (IL-10) the prototypical anti-inflammatory cytokine. IL-10 regulation is dependent in part on the activation of Akt. The effects of BV on IL-10 expression are lost with blockade of Akt. Inhibition of surface BVR with RNA interference attenuates BV-induced Akt signaling and IL-10 expression and in vivo negates the cytoprotective effects of BV in models of shock and acute hepatitis. Collectively, our findings elucidate a potentially important new molecular mechanism by which BV, through the enzymatic activity and phosphorylation of surface BVR (BVR) surf modulates the inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt

Węgiel

Baty

Gallo

et al. 2009

Journal of Biological Chemistry

138

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“…The significance of hBVR phosphorylation by PKC␦ can be viewed in the context of its role in the cellular defense mechanisms against free radicals. As noted above, activation of hBVR can significantly influence those cellular functions that extend beyond its role in the cellular defense mechanisms (5,6,12,14,25,42,67).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its role in cell growth and apoptotic processes, PKC␦ has been implicated in regulation of membrane ion channels, activation of transcriptional factors, antigen presentation, and with various cancers (3). hBVR, 2 a Ser/Thr/Tyr kinase and a reductase, is a 296-residue soluble polypeptide with an extensive range of input into signal transduction pathways, as well as being a key component of cellular defense mechanisms (4); the reductase activity of hBVR is directly associated with its phosphorylation state (5,6). Depending on the type of stimulus and cell type, activation of PKC␦ and hBVR can exert opposing effects on apoptotic events or bring about a similar outcome on cell survival.…”

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confidence: 99%

The Human Biliverdin Reductase-based Peptide Fragments and Biliverdin Regulate Protein Kinase Cδ Activity

Miralem

Lerner-Marmarosh

Gibbs

et al. 2012

Journal of Biological Chemistry

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Background: hBVR reduces biliverdin to antioxidant bilirubin. PKC␦ promotes tumorigenesis and apoptosis. Results: Complex formation between PKC␦ and hBVR results in transactivation. hBVR-based peptides are identified as substrates or inhibitors of the PKC in vitro and in the cell. Biliverdin inhibits PKC␦. Conclusion: A regulatory loop links PKC␦ and hBVR in cell signaling. Significance: hBVR-based peptides can be used to regulate PKC␦ signaling.

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“…24 The S/T/Y (serine/threonine/tyrosine) kinase activity of hBVR has been linked to its function in the insulin/IGF receptor signaling cascade in both the MAPK and PI3K branches, 25,26 and its DNA binding has been shown to involve its bZip domain. [27][28][29] hBVR, as with other members of this family of AP-1/CRE binding transcription factors: c-Jun, c-Fos, c-Myc and CREB/ATF-2, is activated by free radicals. Its activation is demonstrably a determining factor in response of ho-1 to oxidative stress 23 and hence bilirubin production and hBVR activation also influence glucose uptake 26 as well as CREB/ATF-2 gene expression.…”

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Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

Gibbs

Maines

2007

Intl Journal of Cancer

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hBVR functions in the cell as a reductase and as a kinase. In the first capacity, it reduces biliverdin, the product of HO activity, to the effective intracellular antioxidant, bilirubin; as a dual-specificity kinase (S/T/Y) it activates the MAPK and IGF/IRK receptor signal transduction pathways. NF-jB and the MAPK pathway are activated by ROS, which results in the activation of stress-inducible genes, including ho-1. Presently, we report on the negative effect of biliverdin on NF-jB activation and the converse effect of hBVR. Biliverdin, in a concentration-and time-dependent manner, inhibited transcriptional activity of NF-jB in HEK293A cells. Nuclear extracts from biliverdin-treated cells show reduced DNA binding of NF-jB in an electromobility shift assay, whereas extracts from cells treated with TNF-a showed enhanced binding. Coimmunoprecipitation data show hBVR binds to the 65 kDa subunit of NF-jB, and that this is dependent on activation by TNF-a. Overexpression of hBVR enhanced both the basal and TNF-amediated activation of NF-jB and also that of the NF-jB-activated iNOS gene. Also, overexpression of hBVR arrested the cell cycle in the G 1 /G 0 phase and reduced the number of cells in S phase. Similar results were observed with MCF-7 cells. Because of the Janus nature of NF-jB activity in the cell and the inhibitory action of biliverdin, the present findings provide a foundation for therapeutic intervention in inflammatory diseases and cancer that may be attained by preventing reduction of biliverdin. On the other hand, by increasing BVR levels beneficial functions of NF-jB might be augmented. ' 2007 Wiley-Liss, Inc.

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Human Biliverdin Reductase Is a Leucine Zipper-like DNA-binding Protein and Functions in Transcriptional Activation of Heme Oxygenase-1 by Oxidative Stress

Abstract: . ) formed by menadione is attenuated, whereas induction by heme is not affected. We propose a role for BVR in the signaling cascade for AP-1 complex activation necessary for HO-1 oxidative stress response.

Cited by 93 publications

References 49 publications

Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt

Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt

The Human Biliverdin Reductase-based Peptide Fragments and Biliverdin Regulate Protein Kinase Cδ Activity

Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

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