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PMID: 11134536 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 1 ·2001-01-02 ·Pages 48-53

Akiyama T, Takasawa S, Nata K, Kobayashi S, Abe M, Shervani NJ, Ikeda T, Nakagawa K, Unno M, Matsuno S, Okamoto H

Abstract

The regeneration of pancreatic islet beta 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 beta-cell replication via the Reg receptor and ameliorates experimental diabetes. However, the mechanism by which Reg gene is activated in beta 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 beta cells and that PARP inhibitors enhanced the expression. Reporter gene assays revealed that the -81 approximately -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.

MeSH Terms
Animals Base Sequence Calcium-Binding Proteins/genetics Cell Line DNA/genetics,metabolism DNA Repair/genetics DNA-Binding Proteins/analysis,metabolism Dexamethasone/pharmacology Gene Expression Regulation/drug effects Immunoblotting Insulin/metabolism Interleukin-6/pharmacology Islets of Langerhans/cytology,metabolism Lithostathine Models, Biological Nerve Tissue Proteins Poly Adenosine Diphosphate Ribose/metabolism Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases/metabolism Promoter Regions, Genetic/genetics Protein Binding Rats Regeneration/genetics Response Elements/genetics Transcription, Genetic/drug effects
Chemicals
Calcium-Binding Proteins DNA-Binding Proteins Insulin Interleukin-6 Lithostathine Nerve Tissue Proteins Poly(ADP-ribose) Polymerase Inhibitors Reg1a protein, rat Poly Adenosine Diphosphate Ribose Dexamethasone DNA Poly(ADP-ribose) Polymerases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Akiyama T
Departments of Biochemistry and Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan.
Takasawa S
Nata K
Kobayashi S
Abe M
Shervani N J
Ikeda T
Nakagawa K
Unno M
Matsuno S
Okamoto H
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.240458597
Published
2001-01-02
Pages
48-53
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC14542
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.240458597 PMC Full Text View journal details
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