Pleiotropic functions of biliverdin reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin.
Degradation of heme requires its conversion to biliverdin (BV) by heme oxygenase, followed by reduction of BV to the free-radical quencher bilirubin (BR) by biliverdin reductase (BVR). It is now recognized that human BVR (hBVR) is a dual-specificity kinase (Ser/Thr and Tyr) upstream activator of the insulin/insulin growth factor-1 (IGF-1) and mitogen-activated protein kinase (MAPK) signaling pathways. hBVR is also a basic-leucine-zipper (bZip) DNA/chromatin-binding transcription factor, an activator and anchor protein for translocation of protein kinase C betaII and zeta isozymes within cell compartments, and a kinase kinase for their activation. hBVR is essential for MAPK-extracellular signal-regulated kinase (ERK)1/2 (MEK)-eukaryotic-like protein kinase (Elk) signaling and has been identified as the cytoplasm-nuclear heme transporter of ERK1/2 and hematin, the key components of stress-responsive gene expression. Here, we discuss the recently uncovered functions of hBVR in cell signaling and regulation of gene expression, and the role of BR in cellular signaling, cytoprotection and cytotoxicity.
Kapitulnik
Jaime
J
Department of Pharmacology, the David R. Bloom Center for Pharmacy, School of Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem, Israel. jaimek@savion.huji.ac.il
Maines
Mahin D
MD
D001654:Bile Pigments / Q000502:physiology; D001663:Bilirubin / Q000502:physiology*; D019610:Cytoprotection; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology; D015398:Signal Transduction
D001654:Bile Pigments; D007328:Insulin; D016328:NF-kappa B; D007334:Insulin-Like Growth Factor I; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D001663:Bilirubin