PCAF represses transactivation function of FOXO1 in an acetyltransferase-independent manner.
The FOXO transcription factors play a key role in cell cycle control, apoptosis, DNA repair, oxidative stress resistance, and longevity. In this study, we demonstrated that the acetyltransferase p300/CBP associated factor (PCAF) functions as a negative regulator of FOXO1. We showed that PCAF bound to the forkhead domain of FOXO1 and acetylated FOXO1 at the K242 and K245 residues. However, PCAF repressed FOXO1-induced transcription in an enzymatic activity-independent manner. In contrast, the transcriptional activity of FOXO1 S253A mutant, in which an Akt phosphorylation site is replaced by alanine, was not repressed by PCAF. Akt-induced phosphorylation of FOXO1 is required for its binding to PCAF, whereas the binding between FOXO1 and CBP is independent on FOXO1 S253 phosphorylation. Furthermore, overexpression of PCAF increased nuclear accumulation of FOXO1 even in the presence of serum. These results suggest that PCAF binds to phosphorylated FOXO1 by Akt and acts as a transcriptional corepressor in the nucleus.
Yoshimochi
Kenji
K
Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Daitoku
Hiroaki
H
Fukamizu
Akiyoshi
A
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C085126:FOXO1 protein, human