Induction of Mxi1-SRα by FOXO3a contributes to repression of Myc-dependent gene expression
Induction of Mxi1-SRα by FOXO3a contributes to repression of Myc-dependent gene expression
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DOI：
10.1128/mcb.01789-06
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发表时间：
2007-07-01
影响因子：
5.3
通讯作者：
Schulze, Almut
中科院分区：
文献类型：
--
作者：
Delpuech, Oona;Griffiths, Beatrice;Schulze, Almut
O类叉头转录因子（FOXO）是磷脂酰肌醇3-激酶（PI 3-kinase）/Akt通路的重要靶点。FOXO与细胞周期进程、抗氧化应激和细胞凋亡的调节有关。使用DNA微阵列，我们分析了转录响应FOXO 3a激活的基因表达分析在DLD-1结肠癌细胞稳定表达FOX 03 a。A3-ER融合蛋白。我们发现FOX 03 a的激活导致了许多先前鉴定的Myc靶基因的抑制。此外，FOX 03 a的激活诱导的几个成员的Mad/Mxd家族的转录抑制因子，最显着的Mxi 1的表达。FOX 03 a对Mxi 1的诱导是Mxi 1-SRa亚型特异性的，并且由该基因第一内含子内的三个高度保守的FOXO结合位点介导。响应于Akt的抑制的FOX 03 a的激活也导致Mxi 1-SRa表达的激活。通过小干扰RNA（siRNA）沉默Mxi 1减少了FOX 03 a介导的对许多Myc靶基因的抑制。我们还观察到，FOX 03 a激活诱导启动子占据从Myc到Mxi 1的转换，在包含两个Myc靶基因APEX和FOXM 1的启动子区域的E-box上。SiRNA介导的Mxi 1或所有Mad/Mxd蛋白的瞬时沉默减少了FOX 03 a激活后从S期的退出，而Mxi 1或Mad 1的稳定沉默则减少了FOX 03 a的生长抑制作用。我们的结论是，Mad/Mxd蛋白的诱导有助于响应于FOX 03 a激活的增殖抑制。我们的研究结果提供了FOX 03 a直接调节Mxi 1的证据，并暗示了PI 3-激酶/Akt/FOXO通路可以调节Myc功能的另一种机制。
Forkhead transcription factors of the O class (FOXOs) are important targets of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. FOXOs have been implicated in the regulation of cell cycle progression, oxidative stress resistance, and apoptosis. Using DNA microarrays, we analyzed the transcriptional response to FOXO3a activation by gene expression analysis in DLD-1 colon cancer cells stably expressing a FOX03a. A3-ER fusion protein. We found that activation of FOX03a resulted in repression of a number of previously identified Myc target genes. Furthermore, FOX03a activation induced expression of several members of the Mad/Mxd family of transcriptional repressors, most notably Mxi1. The induction of Mxi1 by FOX03a was specific to the Mxi1-SRa isoform and was mediated by three highly conserved FOXO binding sites within the first intron of the gene. Activation of FOX03a in response to inhibition of Akt also resulted in activation of Mxi1-SRa expression. Silencing of Mxi1 by small interfering RNA (siRNA) reduced FOX03a-mediated repression of a number of Myc target genes. We also observed that FOX03a activation induced a switch in promoter occupancy from Myc to Mxi1 on the E-box containing promoter regions of two Myc target genes, APEX and FOXM1. siRNA-mediated transient silencing of Mxi1 or all Mad/Mxd proteins reduced exit from S phase in response to FOX03a activation, and stable silencing of Mxi1 or Mad1 reduced the growth inhibitory effect of FOX03a. We conclude that induction of Mad/Mxd proteins contributes to the inhibition of proliferation in response to FOX03a activation. Our results provide evidence of direct regulation of Mxi1 by FOX03a and imply an additional mechanism through which the PI3-kinase/Akt/FOXO pathway can modulate Myc function.