Keiko HIROTA    Department   School of Medicine, School of Medicine    Position   Assistant Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor.
Journal	Formal name：The Journal of biological chemistry Abbreviation：J Biol Chem ISSN code：00219258/1083351X
Domestic / Foregin	Foregin
Volume, Issue, Page	278(15),pp.13056-13060
Author and coauthor	HIROTA Keiko†, DAITOKU Hiroaki, MATSUZAKI Hitomi, ARAYA Natsumi, YAMAGATA Kazuyuki, ASADA Sachie, SUGAYA Takeshi, FUKAMIZU Akiyoshi*
Publication date	2003/04
Summary	Previous studies have shown that FKHR, a member of the forkhead family of transcription factors, acts as a DNA binding-independent cofactor of nuclear receptors, including estrogen, retinoid, and thyroid hormone receptors, in addition to the original function as a DNA binding transcription factor that redistributes from the nucleus to the cytoplasm by insulin-induced phosphorylation. Here, we demonstrated the physical interaction of FKHR with hepatocyte nuclear factor (HNF)-4, a member of steroid/thyroid nuclear receptor superfamily, and the repression of HNF-4 transactivation by FKHR. FKHR interacted with the DNA binding domain of HNF-4 and inhibited HNF-4 binding to the cognate DNA. Furthermore, the binding affinity of HNF-4 with phosphorylated FKHR significantly decreased in comparison to that with unphosphorylated FKHR. Therefore, a phosphorylation of FKHR by insulin followed by its dissociation from HNF-4 and the redistribution of FKHR from the nucleus to the cytoplasm would expect to induce the transcriptional activation of HNF-4 by facilitating to the access of HNF-4 to its DNA element. Indeed, most intriguingly, insulin stimulation reversed the repression of HNF-4 transcriptional activity by phosphorylation-sensitive (wild-type) FKHR, but not by phosphorylation-deficient FKHR. These results suggest that insulin regulates the transcriptional activity of HNF-4 via FKHR as a signal-regulated transcriptional inhibitor.