The heme metabolic pathway is exquisitely responsive to environmental agents, including metal and porphyrin complexes. Biliverdin reductase (BVR) catalyzes the final step in the pathway. In the past BVR, its substrate, biliverdin, and its product (bilirubin) were considered solely in context of disposal of heme degradation products. Recent findings have alluded to their relevance to a wide range of functions in the cell. Bilirubin is an intracellular antioxidant; biliverdin, product of HO-1 and HO-2 activity, suppresses gene expression and underlies the frequently morbid """"""""green jaundice."""""""" During the past funding period we demonstrated human BVR is a major component of signal transduction pathways: it is a serine/threonine /tyrosine kinase that is activated by phosphorylation in response to oxidative stress and translocates into the nucleus in response to free radicals, cytokines and cAMP, and in tumorigenesis. In the nucleus, BVR functions as a regulator for expression of AP-1 and cAMP target genes that includes HO-1, c-Jun, and ATF-2/CREB.Gene array analysis identifies other genes crucial to signaling and cytoprotection affected by BVR. BVR is a leucine-zipper transcription factor that binds to AP-1 site; biliverdin inhibits its DNA binding. BVR is a substrate for insulin receptor kinase (IRK), is a kinase for IR substrate and, protects against As (III)- mediated apoptosis. Initial studies show: BVR activates PKC, has PKB/Akt activity, binds to PKC and ERK1/2, and promotes cell differentiation; the effects are not cell line specific. Collectively, these findings reveal a previously unrecognized vital component of cell signaling and cytoprotection. The overall objective of this application is to investigate the mechanism and consequences of BVR modulation of cell signaling by the two major arms of insulin receptor/growth factor cascade: the phosphoinositol-3-kinase (PI3-K) and MAPK/ERK pathways, which are linked by PKC. To achieve this objective, 4 aims are proposed: 1) To define role of BVR in the IRK-mediated activation of PI3-K component of insulin/IGF-1 signaling pathway; 2) To examine regulation of MAPK/ERK component of this pathway by BVR; 3) To further define activation of PKC enzymes by BVR; and, 4) To examine in vivo regulation of insulin/IGF signaling by BVR and biliverdin. For this, mice null for BVR gene will be generated to examine effects of phenylhydrazine and As (III), which are diabetogenic and promote cell death, on glucose metabolism and apoptosis.
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