Potential Application of Biliverdin Reductase and its Fragments to Modulate insulin/IGF-1/MAPK/PI3-K Signaling Pathways in Therapeutic Settings

The range and diversity of functions of biliverdin reductase (BVR) are unmatched by any enzyme characterized to date. BVR is the sole catalyst for the conversion of biliverdin-IXα, the activity product of the stress-inducible HO-1 and the constitutive HO-2, to bilirubin-IXα. Bilirubin is both cytoprotective and cytotoxic, quenches reactive oxygen species (ROS) and inhibits inflammatory and mitogen-induced ROS-mediated responses, and its elevated levels in the newborn adversely effect neuronal cells. Thus, BVR occupies a center stage in cellular defense mechanisms. As a dual specificity (serine/threonine/tyrosine) kinase the human (h) BVR influences transduction of extracellular stimuli to kinases downstream of the insulin/IGF-1(insulin-like growth factor-1)/MAPK/PI3-K signaling pathways. As a bZip-type transcription factor it binds to AP-1 (activator protein-1) and CRE (cAMP response element) sites and stimulates stressinducible gene expression; as a scaffold protein, it is a platform for interaction of kinases; while acting as an intracellular shuttle, it transports regulatory factors to their target sites. hBVR promoter has consensus sequences with several regulatory elements. The gene is subject to negative and positive regulation, respectively, by TNF-α (tumor necrosis factor-α) and oxidative stress/hypoxia. Small human BVR-based peptides effectively duplicate polypeptide's activating influence on kinases, or mimic inhibitors of cell signaling. This, points to a realistic prospect of their use in clinical settings. The present review will briefly update cytoprotective activity and cytotoxicity of bile pigments and will focus on findings that link hBVR to cell signaling.