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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor.

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.[1]

References

  1. Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor. Hirota, K., Daitoku, H., Matsuzaki, H., Araya, N., Yamagata, K., Asada, S., Sugaya, T., Fukamizu, A. J. Biol. Chem. (2003) [Pubmed]
 
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