Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression.
Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression.
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DOI：
10.1093/nar/gkr638
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发表时间：
2011-12
影响因子：
14.9
通讯作者：
Majello B
中科院分区：
文献类型：
--
作者：
Amente S;Zhang J;Lavadera ML;Lania L;Avvedimento EV;Majello B
生长因子撤除通过激活FOXO3a等Forkhead box O转录因子来刺激生长抑制基因的表达，从而抑制细胞周期进展，FOXO3a与PUMA和GADD45a等靶基因的FHRE反应元件结合。在细胞暴露于生长因子后，FOXO3a介导的转录被迅速抑制。我们确定抑制与PI3K/AKT通路激活导致FOXO3a磷酸化和FOXO3a蛋白从PUMA和GADD45a染色质释放有关。我们在这里表明，Myc显著和选择性地抑制FOXO介导的PUMA和GADD45a的表达。我们发现，在Myc缺失的细胞中，血清刺激后PUMA和GADD45a的抑制受到损害，并且Myc不干扰P53诱导PUMA转录。我们观察到，激活后，Myc迅速招募到PUMA和GADD45a染色质，伴随着启动子占据从FOXO3a到Myc的切换。MYC募集刺激PUMA和GADD45染色质上组蛋白H3和H4的脱乙酰化以及H3(H3K9me2)中赖氨酸9的甲基化。这些数据强调了Myc通过选择性地抑制FOXO3a诱导的PUMA和GADD45的转录而在细胞生长中的作用。
Growth factor withdrawal inhibits cell cycle progression by stimulating expression of growth-arresting genes through the activation of Forkhead box O transcription factors such as FOXO3a, which binds to the FHRE-responsive elements of a number of target genes such as PUMA and GADD45a. Following exposure of cells to growth factors FOXO3a-mediated transcription is rapidly repressed. We determined that repression correlates with activation of PI3K/AKT pathway leading to FOXO3a phosphorylation and release of FOXO3a protein from PUMA and GADD45a chromatin. We show here that Myc significantly and selectively contributes to repression of FOXO-mediated expression of PUMA and GADD45a. We found that in Myc deprived cells inhibition of PUMA and GADD45a following serum stimulation is impaired and that Myc does not interfere with p53 induction of PUMA transcription. We observed that following activation, Myc is rapidly recruited to PUMA and GADD45a chromatin, with a concomitant switch in promoter occupancy from FOXO3a to Myc. Myc recruitment stimulates deacetylation of Histone H3 and H4 and methylation of lysine 9 in H3 (H3K9me2) on both PUMA and GADD45 chromatin. These data highlight a Myc role on cell growth by selectively inhibiting FOXO3a induced transcription of PUMA and GADD45.
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