Yoshimochi Kenji, Daitoku Hiroaki, Fukamizu Akiyoshi
Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
J Recept Signal Transduct Res. 2010 Feb;30(1):43-9. doi: 10.3109/10799890903517947.
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.
FOXO转录因子在细胞周期调控、细胞凋亡、DNA修复、抗氧化应激及寿命延长方面发挥关键作用。在本研究中，我们证明了乙酰转移酶p300/CBP相关因子（PCAF）作为FOXO1的负调控因子发挥作用。我们发现PCAF与FOXO1的叉头结构域结合，并使FOXO1的K242和K245残基发生乙酰化。然而，PCAF以一种不依赖酶活性的方式抑制FOXO1诱导的转录。相反，Akt磷酸化位点被丙氨酸取代的FOXO1 S253A突变体的转录活性不受PCAF抑制。Akt诱导的FOXO1磷酸化是其与PCAF结合所必需的，而FOXO1与CBP之间的结合不依赖于FOXO1的S253磷酸化。此外，即使在有血清存在的情况下，PCAF的过表达也会增加FOXO1的核内积累。这些结果表明，PCAF与Akt磷酸化的FOXO1结合，并在细胞核中作为转录共抑制因子发挥作用。
