Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation.
AFX (also called Foxo4), a member of mammalian FOXO forkhead transcription factors, is the homolog of DAF-16, which contributes longevity and oxidative stress in Caenorhabditis elegans. Here, we show that CREB-binding protein (CBP) interacts with AFX via CH1 region and acetylates it at the three lysine residues (K186, K189, and K408). Trichostatin A (TSA) repressed the AFX-stimulated transcription, and substitution of the lysine residues with arginine (K186, 189, 408R) enhanced the transcriptional activity of AFX. Furthermore, TSA suppressed the expression of p27kip1 gene induced by AFX in HEK293T cells. Compared to the coexpression of CBP wild-type, a HAT activity-deficient mutant (DeltaHAT) efficiently leads the cooperative activation of AFX transcription in HepG2 cells. Taken together, these results demonstrate that CBP-induced acetylation of AFX is a novel modification mechanism by which AFX keeps the transcriptional activity mitigating in the nucleus.
Fukuoka
Masahiro
M
Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Daitoku
Hiroaki
H
Hatta
Mitsutoki
M
Matsuzaki
Hitomi
H
Umemura
Satoshi
S
Fukamizu
Akiyoshi
A
D000818:Animals; D001120:Arginine / Q000737:chemistry; D015153:Blotting, Western; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry; D008957:Models, Genetic; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C012589:trichostatin A; D001120:Arginine; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D005982:Glutathione Transferase; D008239:Lysine