Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells.
Forkhead box O1 (FOXO1) is an important target for insulin. It is widely accepted that insulin-induced phosphorylation of FOXO1 by Akt leads to its nuclear exclusion and results in the inhibition of FOXO1-mediated transcription of the gluconeogenic gene phosphoenolpyruvate carboxykinase 1 (PCK1) in hepatocytes. However, many results that contradict this model have accumulated. Here, we provide a new mechanism for insulin-dependent repression of FOXO1-mediated transcription. We showed insulin-induced translocation of endogenous Ser256-phosphorylated FOXO1, which is essential for regulation of FOXO1-mediated transcription, from nuclear speckles to the nuclear periphery. This insulin-dependent translocation of FOXO1 regulated transcriptional repression of PCK1 concomitant with the formation of the FOXO1-euchromatic histone-lysine N-methyltransferase2 (EHMT2) complex and histone modifications of the PCK1 promoter region. Notably, our results suggest that FOXO1 uses nucleoporin 98 kDa NUP98 for this transcriptional regulation. These results provide a new insight into various FOXO1-mediated transcriptional regulation and FOXO1-mediated essential biological pathways.
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo, 153-8902, Japan.
Tamaki
T
Arai
Fumi
F
Kano
Masayuki
M
Murata
D002467:Cell Nucleus / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D056945:Hep G2 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D028884:Karyopherins / Q000378:metabolism; D008745:Methylation; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D014158:Transcription, Genetic; D000097606:Exportin 1 Protein
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D018160:Receptors, Cytoplasmic and Nuclear; D012261:Ribonucleoproteins; D012694:Serine; D000068103:Serine-Arginine Splicing Factors; D000097606:Exportin 1 Protein; C085126:FOXO1 protein, human; C465451:Nup98 protein, human; C073288:SRSF2 protein, human; C521898:PCK1 protein, human