Biliverdin reductase (BVR) is a unique dual pH/cofactor-dependent enzyme that catalyzes the last step in the heme degradation pathway (i,e reduction of biliverdin to bilirubin). Biliverdin, the substrate for BVR, is generated, with carbon monoxide (CO), in the course of heme degradation by the stress/heat shock family of proteins: heme oxygenase (HO)-1 and HO-2. CO functions as NO. BVR is the ultimate regulator of heme metabolism, in that, biliverdin regulates HO activity in vivo. Biliverdin is also a liver tumor promoter and inhibits human Herpes virus-6 replication and HIV-1 proliferation. Bilirubin is a potent antioxidant; low levels of serum bilirubin are associated with increased risk of coronary artery heart disease and retinopathy of prematurity. We are the only laboratory in the country actively pursuing molecular toxicology research on BVR that, by virtue of being an -SH-dependent enzyme, is a target for environmental agents and nephrotoxins. We have now discovered that BVR is a kinase and a protein kinase C (PKC)-interacting and -activating protein and translocates into the nucleus in response to nephrotoxins: such as mercury, bromobenzene and bacterial endotoxins (LPS) as well as in cancerous transformation. In addition, in human kidney tumors, ischemic rat brain and kidneys, and in kidneys of rats exposed to nephrotoxins, BVR levels are increased. Also, the ability to produce biliverdin in advanced human prostate tumor cells is increased. PKCs play an important role in the field of cancer research and are key components of cellular response to oxidative stress. Based on the ability of BVR to activate PKC, it is likely that BVR plays a significant role in modulating a multitude of cellular functions including cell growth and differentiation.
The Specific Aims of the proposed studies are 1) To further characterize BVR for molecular properties and requirements of kinase and reductase activities. 2) To further investigate BVR/PKC interaction. 3) To characterize BVR interactive proteins in the cells and to identify the proteins that interact with BVR under normal and oxidative stress conditions, such as exposure to nephrotoxic agents and cancer. Also, to explore the nuclear function of BVR in the context of HO-1's response to oxidative stress. 4) To isolate the human BVR gene, characterize its promoter region and analyze its regulation by various toxins and effector agents.
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