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

Takako Akiyama, Shin Takasawa, Koji Nata, Seiichi Kobayashi, Michiaki Abe, Nausheen J. Shervani, Takayuki Ikeda, Kei Nakagawa, Michiaki Unno, Seiki Matsuno, Hiroshi Okamoto

Research output: Contribution to journalArticlepeer-review

156 Citations (Scopus)

Abstract

The regeneration of pancreatic islet β cells is important for the prevention and cure of diabetes mellitus. We have demonstrated that the administration of poly(ADP-ribose) synthetase/polymerase (PARP) inhibitors such as nicotinamide to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library, we have isolated Reg (regenerating gene) and demonstrated that Reg protein induces β-cell replication via the Reg receptor and ameliorates experimental diabetes. However, the mechanism by which Reg gene is activated in β cells has been elusive. In this study, we found that the combined addition of IL-6 and dexamethasone induced the expression of Reg gene in β cells and that PARP inhibitors enhanced the expression. Reporter gene assays revealed that the -81 ≈ -70 region (TGCCCCTCCCAT) of the Reg gene promoter is a cis-element for the expression of Reg gene. Gel mobility shift assays showed that the active transcriptional DNA/protein complex was formed by the stimulation with IL-6 and dexamethasone. Surprisingly, PARP bound to the cis-element and was involved 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 complex formation for Reg gene transcription and stabilize the complex by inhibiting the autopoly(ADP-ribosyl)ation of PARP.

Original languageEnglish
Pages (from-to)48-53
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number1
DOIs
Publication statusPublished - 2001 Jan 2

ASJC Scopus subject areas

  • General

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