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PMID: 9121428 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Characterization of a novel protein kinase C response element in the glucagon gene.

Molecular and cellular biology ·Vol. 17 ·No. 4 ·1997-04-00 ·Pages 1805-16

Fürstenau U, Schwaninger M, Blume R, Kennerknecht I, Knepel W

Abstract

To maintain glucose levels in blood within narrow limits, the synthesis and secretion of pancreatic islet hormones are controlled by a variety of neural, hormonal, and metabolic messengers that act through multiple signal transduction pathways. Glucagon gene transcription is stimulated by cyclic AMP and depolarization-induced calcium influx. In this study, the effect of protein kinase C on glucagon gene transcription was investigated. After transient transfection of a glucagon-reporter fusion gene into the glucagon-producing islet cell line alphaTC2, activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated glucagon gene transcription. By 5' deletions, 3' deletions, internal deletion, and oligonucleotide cassette insertion, the TPA-responsive element was mapped to the G2 element (from -165 to -200). Like TPA, overexpression of oncogenic Ras (V-12 Ras) stimulated G2-mediated transcription whereas overexpression of a dominant negative Ras mutant (N-17 Ras) blocked the effect of TPA. A mutational analysis of G2 function and nuclear protein binding indicated that protein kinase C and Ras responsiveness is conferred to the glucagon gene by HNF-3beta functionally interacting with a protein that binds to a closely associated site with sequence similarity to binding sites of Ets family proteins. HNF-3beta belongs to the winged-helix family of transcription factors and has been implicated in the control of cell-specific and developmental gene expression. The results of the present study show that the cell lineage-specific transcription factor HNF-3beta is an essential component of a novel protein kinase C response element in the glucagon gene.

MeSH Terms
Animals Base Sequence Binding Sites Calcium/pharmacology Cell Line Chromosome Mapping Cyclic AMP/pharmacology DNA Mutational Analysis DNA-Binding Proteins/metabolism Enzyme Activation/drug effects Glucagon/genetics Hepatocyte Nuclear Factor 3-beta Islets of Langerhans/drug effects,metabolism Mice Nuclear Proteins/metabolism Oligodeoxyribonucleotides/genetics Protein Kinase C/metabolism Tetradecanoylphorbol Acetate/pharmacology Transcription Factors/metabolism Transcription, Genetic/drug effects ras Proteins/metabolism
Chemicals
DNA-Binding Proteins Foxa2 protein, mouse Nuclear Proteins Oligodeoxyribonucleotides Transcription Factors Hepatocyte Nuclear Factor 3-beta Glucagon Cyclic AMP Protein Kinase C ras Proteins Tetradecanoylphorbol Acetate Calcium
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fürstenau U
Department of Molecular Pharmacology, University of Göttingen, Germany.
Schwaninger M
Blume R
Kennerknecht I
Knepel W
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.17.4.1805
Published
1997-04-00
Pages
1805-16
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC232027
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.17.4.1805 PMC Full Text View journal details
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