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Research Projects

Formation of a Ternary Complex of Human Biliverdin Reductase/ PKC-δ/ ERK2

Formation of a Ternary Complex of Human Biliverdin Reductase/ PKC-δ/ ERK2We have shown for the first time that human biliverdin reductase (hBVR) forms a macromolecular complex with protein kinase Cδ and the extracellular receptor kinase, ERK2; and that formation of this complex is required for downstream nuclear signaling mediated by ERK2.

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hBVR's Roles in the Cell Cycle

hBVR's Roles in the Cell CycleCell cycle studies so far have shown that in the presence of IFN-γ, there is an increase in the number of cells in S-phase in GFP-BVR transfected HEK293 cells compared to control GFP cells, or to untreated cells. Our previous studies have shown that over-expression of hBVR led to cell cycle arrest in the G1/G0 phase, with concomitant reduction of S-phase cells.

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hBVR Regulation of STAT1

hBVR Regulation of STAT1Human biliverdin reductase appears to play a regulatory role in IFN-γ mediated signal transduction in normal and cancerous cells. Examination of downstream targets in the signaling pathway has shown that of phosphorylation STAT-1, STAT-3 and Akt were increased within 10 minutes of IFN-γ treatment. IFN-γ also increases BVR mRNA expression within 12 hours of treatment in these cells.

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hBVR and Protein Kinases & Phosphatases

hBVR and Protein Kinases & PhosphatasesTo date, we have focused on those functions of hBVR that result in activation of protein kinases. However, such activation events in the cell are transient, and the phosphorylated targets are inactivated by protein phosphatases. In the course of our studies with the hBVR/PKC-δ/ERK complex, it was found that other proteins were associated with it – notably MEK and the protein phosphatase PP2A.

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Regulation of hBVR Expression

Regulation of hBVR ExpressionIt is apparent that hBVR regulates the activity of multiple pathways in the cell. The protein itself is ubiquitously expressed, but does not appear to respond rapidly at the level of transcription to external stimuli. To date, we have observed that gene expression from the hBVR promoter is up-regulated by hypoxia, and down-regulated by TNF-α (acting through NF-κB).

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Regulation of HO-2

Regulation of HO-2The heme oxygenase-2 protein is also ubiquitously expressed, although the highest levels appear to be in the testis and the brain. In the course of our studies with BVR, it was found that treatment of cardiomyocytes with siRNA against BVR resulted in down-regulation of HO-2, at two levels.

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