title: Recent advances in physiological and pathological significance of tryptophan-NAD+ metabolites: lessons from insulin-producing pancreatic beta-cells.
abstract: In the early 1980s we found that streptozotocin and alloxan, typical diabetogenic agents, induce pancreatic beta-cell DNA strand breaks through the formation of free radicals. The breaks induce DNA repair involving the activation of poly(ADP-ribose) polymerase (PARP), which uses NAD+ as a substrate. As a result, the intracellular levels of NAD+ fall dramatically. The fall in NAD+ inhibits cellular functions including insulin synthesis and secretion, and thus the beta-cell ultimately dies. We subsequently proposed that maintenance of the NAD+ level is essential for the synthesis and secretion of insulin, and presented a unifying model for beta-cell damage and its prevention (The Okamoto model), in which PARP activation plays an essential role. Recently, the model was reconfirmed by experiments using PARP knockout mice and has been recognized as providing the basis for necrotic death of various cells and tissues. In 1993, we found that cyclic ADP-ribose (cADPR), a metabolite of NAD+, is a second messenger for intracellular Ca2+ mobilization for insulin secretion by glucose, and proposed a novel mechanism of insulin secretion, the CD38-cADPR signal system. Recently, various physiological phenomena from animal to plant cells become understandable in terms of this signal system. In 1984, we demonstrated that the administration of PARP inhibitors to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library we found a novel beta-cell growth factor gene, Reg (Regenerating Gene), and elucidated the mechanism of Reg gene expression in beta-cells, in which PARP acts as a transcription factor for Reg gene expression. PARP bound to the cis-element of Reg promoter and formed the active transcriptional DNA/protein complex. The complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance and stabilize the complex formation for Reg gene transcription. Reg protein acts as an autocrine/paracrine growth factor to induce beta-cell replication via the Reg receptor and ameliorates experimental diabetes.
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan. okamotoh@mail.cc.tohoku.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D004260:DNA Repair; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008954:Models, Biological; D009243:NAD / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D015398:Signal Transduction; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D007328:Insulin; D008562:Membrane Glycoproteins; D009243:NAD; D036563:Cyclic ADP-Ribose; D011064:Poly Adenosine Diphosphate Ribose; D014364:Tryptophan; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1