HEPATOCYTE-NUCLEAR FACTOR 3-BETA GENE TRANSCRIPTS GENERATE PROTEIN ISOFORMS WITH DIFFERENT TRANSACTIVATION PROPERTIES ON THE GLUCAGON GENE

Hepatocyte-nuclear factor 3 beta (HNF-3 beta), a member of the HNF-3 gene family, is expressed in glucagon-producing islet cells and represses glucagon gene expression. We show here that at least three different HNF-3 beta transcripts that encode HNF-3 beta protein variants are present in glucagon-producing cells, HNF-3 beta(1), HNF-3 beta(2), and HNF-3 beta(3). Compared with the HNF-3 beta(1) cDNA, HNF-3 beta(2) cDNA lacks sequences of exon 1 while exons 1 and 4 are absent from the HNF-3 beta(3) cDNA. The deduced amino-acid (aa) sequence of HNF-3 beta(2) and HNF-3 beta(3) proteins differs from HNF-3 beta(1) by a 6-aa amino-terminal extension and by the absence of the first 30 aa, respectively. HNF-3 beta(1), HNF-3 beta(2), and HNF-3 beta(3) bind to the major enhancer of the rat glucagon gene G2 with similar affinity. By contrast to HNF-3 beta(1), which represses glucagon gene expression when overexpressed in the glucagon-producing cell line InR1G9, HNF-3 beta(2) and HNF-3 beta(3) do not affect transcriptional activity. Furthermore, cotransfection of HNF-3 beta(2) or HNF-3 beta(3) along with HNF-3 beta(1) decreases the negative effects of HNF-3 beta(1). We conclude that glucagon gene expression may be regulated by the relative abundance of the three different HNF-3 beta variants in alpha-cells.