PCAF represses transactivation function of FOXO1 in an acetyltransferase-independent manner
PCAF represses transactivation function of FOXO1 in an acetyltransferase-independent manner
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DOI：
10.3109/10799890903517947
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发表时间：
2010-02
影响因子：
2.8
通讯作者：
Kenji Yoshimochi;H. Daitoku;A. Fukamizu
中科院分区：
文献类型：
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作者：
Kenji Yoshimochi;H. Daitoku;A. Fukamizu
FOXO转录因子在细胞周期调控、细胞凋亡、DNA修复、抗氧化性和延年益寿等方面发挥着关键作用。在本研究中，我们证明了乙酰基转移酶p300/CBP相关因子(PCAF)是FOXO1的负调控因子。我们发现PCAF结合在FOXO1的叉头区，并在K242和K245残基乙酰化FOXO1。然而，PCAF以非酶活性的方式抑制FOXO1诱导的转录。相反，突变的FOXO1 S253A的转录活性，其中Akt磷酸化位点被丙氨酸取代，不被PCAF抑制。AKT诱导的FOXO1的磷酸化是其与PCAF结合所必需的，而FOXO1与CBP的结合不依赖于FOXO1 S253的磷酸化。此外，即使在血清存在的情况下，PCAF的过表达也增加了FOXO1的核积累。这些结果表明，PCAF通过Akt与磷酸化的FOXO1结合，并在细胞核内作为转录辅阻遏子。
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.