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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAj8svMsgCcLcfTw5en6DF0fh2clnDmENxtWZK6rsuL_g#_6 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAj8svMsgCcLcfTw5en6DF0fh2clnDmENxtWZK6rsuL_g#_5 http://www.w3.org/ns/prov#value GATA1 is a key factor in lineage-specific development of stem cells and may be indicative of a function for BVR in the establishment of gene-expression profiles in developing stem cells. GATA2, a marker of skeletal muscle hypertrophy (44), does not affect BVR transcription. Biliverdin Reductase: An Intracellular Transporter? There is the likelihood that in higher forms of life the conserved COOH-terminal-domain cysteines within the HCX10CC/H motif and the extensive beta- sheet in this domain are involved in interactions with other proteins, sulfhydryl reagents, in Zn/metal binding, and in dimerization; native hBVR is a Zn metalloprotein (27, 36). Functions that are assigned to this cysteine-rich domain include: 1) being the interaction site for het- erodimerization with kinases/signaling molecules and homodimerization (1); 2) its function as a \"molecular switch\" in cell signaling through to -SS- interconversion; and, 3) being the site of interaction with substrate/cofactor and heme (40). The involvement of BVR in intracellular trafficking of signaling factors is consistent with the observation that BVR interacts with the insulin receptor kinase (IRK) domain (29) and localizes into the nucleus upon activation by cGMP (33). The proposed function of BVR in protein:protein interaction and intracellular transport of signaling factors is based on its kinase activity, its primary structural features, and the secondary structure of the COOH-terminal domain as a large beta-sheet made of six strands; such a structure characterizes a monomer-monomer interface site, similar to those found in intracellular-trafficking \"scaffold\" proteins. Notably, two copies of the CX10C motif are present in the C1 domain of PKCs (42, 46). Oxidation of cysteine residues to the disulfide form (or covalently bonding with -SH-reactive compounds) prevents BVR dimerization and reductase activity (27). Homodimeric BVR is incapable of docking with other proteins, and this could arise from exposure to factors that affect the oxidation state of the cell and/or have affinity for sulfhydryls. Protein sulfhydryls are a target for the NO- radical (4), for example. Over two decades ago, when little was known about the primary and secondary structure of BVR, observations were made that were unexplainable at the time but when revisited in light of the current information offer support for the function of cysteine residues in BVR protein:protein interactions. In one study rat BVR was characterized as \"extremely sensitive\" to -SH-reactive reagents, although biliverdin was found to fully protect the enzyme (27). Another observation (16) was the \"interconversion\" of two molecular forms of rat liver BVR; a ~34-kDa form was converted to a larger molecular form (~68 kDa) when rats were treated with -SH-reactive agents. Reduced thioredoxin, an agent that can reduce disulfide bonds to sulfhydryl groups, could reverse the conversion. The larger form was found to lack sensitivity to sulfhydryl reagents. These observations would suggest occurrence of dynamic interchange between mono- and dimeric forms of BVR as the consequence of sulfhydryl disulfide interconversion in vivo. Regulation of Oxidative Response and HO-1 Expression Regulation of HO-1 by means of reductase and transcriptional activities may serve as a paradigm for gene regulation of oxidative-response gene expression by BVR. The first direct link between BVR and HO-1 response was provided by a study that demonstrated nuclear localization of BVR in rat kidneys in response to inducers of HO-1, such as bromobenzene and bacterial LPS (33). BVR nuclear localization is an active process and requires an intact nuclear localization signal (FIGURE 1) (33). 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