1) Analysis of regulatory mechanisms of gene transcription by nutrients and hormones.
We identified a basic helix-loop-helix transcription factor, SHARP-2 (also referred to as the DEC1, Stra13, and BHLHB2), as an insulin-inducible transcription factor in the rat liver fed with a high-carbohydrate diet. Overexpression of SHARP-2 in cultured cells leads to a decrease in the levels of phosphoenolpyruvate carboxykinase mRNA that is a gluconeogenic enzyme gene involving in an elevation of blood glucose level. Thus, we suppose that SHARP-2 is an important transcription factor in the insulin signaling pathway.
We are studying on a screening of the SHARP-2-regulatable genes, an analysis of transcriptional regulatory mechanisms by SHARP-2, and an analysis of transcriptional stimulatory mechanisms of the rat SHARP-2 gene by insulin. As the SHARP-2 is an insulin-inducible transcription factor, an increase of SHARP-2 expression by a bioactive material(s) without insulin is useful for patients of the type II diabetes mellitus (T2DM). We are also doing a search of such a material including food composition.
2) Analysis of regulatory mechanisms of gene transcription in oncogenesis.
We first identified human ZHX1, ZHX2, and ZHX3 transcriptional repressors as members of the zinc-fingers and homeoboxes (ZHX) protein family. These proteins form homo- and hetero-dimers with each other. It has been reported that the A subunit of nuclear factor-Y (NF-YA) activates transcription of the cell growth-related genes. The ZHX family proteins interact with the NF-YA and repress NF-Y-dependent gene transcription.
We are studying on a relationship between cell growth and biological activities of the ZHX family proteins in addition to mechanisms of transcriptional repression by the ZHX family proteins.
3) Screening and characterization of the human type II diabetic candidate genes. (Collaboration)
In a collaboration with Dr. Haruhiko Osawa (University of Ehime), we reported that the G/G genotype of a resistin single-nucleotide polymorphism at -420 increases Japanese T2DM susceptibility by inducing promoter activity through specific binding of Sp1/3. We are doing a screening and characterization of the T2DM candidate genes.