Activation of Reg gene, a gene for insulin-producing beta-cell regeneration: Poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation

The regeneration of pancreatic islet beta cells is important for the preven tion and cure of diabetes mellitus. We have demonstrated that the administr ation of poly(ADP-ribose) synthetase/polymerase (PARP) inhibitors such as n icotinamide to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library, we have isolated Reg (regeneratin g gene) and demonstrated that Reg protein induces beta -cell replication vi a the Reg receptor and ameliorates experimental diabetes. However, the mech anism by which Reg gene is activated in beta cells has been elusive. In thi s study, we found that the combined addition of IL-6 and dexamethasone indu ced the expression of Reg gene in beta cells and that PARP inhibitors enhan ced the expression. Reporter gene assays revealed that the -81 approximate to -70 region (TGCCCCTCCCAT) of the Reg gene promoter is a cia-element for the expression of Reg gene. Gel mobility shift assays showed that the activ e transcriptional DNA/protein complex was formed by the stimulation with IL -6 and dexamethasone. Surprisingly, PARP bound to the cis-element and was i nvolved in the active transcriptional DNA/protein complex. The DNA/protein complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance the DNA/protein comp lex formation for Reg gene transcription and stabilize the complex by inhib iting the autopoly(ADP-ribosyl)ation of PARP.