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02 May 2003

Reg (Regenerating Gene) expression by PARP and NF-kB

H. Okamoto, T. Akiyama, K. Nata, T. Ikeda, N. Shervani, S. Kawaguchi, A. Yamauchi, T. Onogawa, N. Noguchi, S. Takasawa

Med Sci Monit 2003; 9(1): 50-0 :: ID: 15113

Abstract

In 1981, we proposed that maintenance of the cellular NAD level in b-cells of pancreatic islets is essential for the synthesis and secretion of insulin and for the repair of b-cell injuries, and presented a unifying model for b-cell damage and its prevention (The Okamoto model), in which PARP activation plays an essential role in the depletion of NAD. In 1984, we demonstrated that the administration of PARP inhibitors to 90% depancreatized rats induces islet b-cell regeneration. From the regenerating islet-derived cDNA library we isolated Reg (Regenerating Gene) and demonstrated that Reg protein produced by Reg induces b-cell replication via the Reg receptor and ameliorates experimental diabetes. Recently, we showed that the combined addition of IL-6 and dexamethasone (Dx) induces the Reg gene expression in b-cells and that PARP inhibitors enhance the expression. PARP bound to the cis-element of Reg promoter and formed the active transcriptional DNA/protein complex upon stimulation by IL-6 and Dx. The formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex and by the addition of an antibody against NF-kB. Overexpression of a mutated form of IkB with a serine-to-alanine mutation at residues 32 and 36 as well as the addition of inhibitors for IkB kinase abrogated the Reg gene transcription in response to IL-6/Dx stimulation. Thus, PARP forms the complex for Reg gene transcription with NF-kB. Therefore, the NF-kB activation as well as PARP inhibition could be new therapeutic approaches for b-cell regeneration.

Keywords: pancreatic b-cells, Okamoto model, Necrosis, Reg, Regeneration, NF-kB

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750