Repression of SRF target genes is critical for Myc‐dependent apoptosis of epithelial cells
Repression of SRF target genes is critical for Myc‐dependent apoptosis of epithelial cells
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DOI：
10.15252/embj.201490467
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发表时间：
2015-06
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影响因子：
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通讯作者：
Katrin E. Wiese;Heidi M. Haikala;B. Eyss;E. Wolf;C. Esnault;A. Rosenwald;R. Treisman;J. Klefström;M. Eilers
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文献类型：
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作者：
Katrin E. Wiese;Heidi M. Haikala;B. Eyss;E. Wolf;C. Esnault;A. Rosenwald;R. Treisman;J. Klefström;M. Eilers
Myc表达的致癌水平使细胞对多种凋亡刺激敏感，这保护了长寿生物体免于癌症发展。细胞如何区分Myc的生理水平和超生理水平在很大程度上是未知的。在这里，我们表明，诱导乳腺上皮细胞中的Myc凋亡需要Myc与Miz 1的关联。基因表达和ChIP测序实验表明，高水平的Myc侵入与Miz 1复合物中缺乏共有E盒的靶位点，并抑制转录。Myc/Miz 1抑制基因编码参与细胞粘附和迁移的蛋白质，包括几种整合素。阻遏基因的启动子富含血清反应因子（SRF）的结合位点。恢复SRF活性可拮抗Myc对SRF靶基因的抑制，减弱Myc诱导的细胞凋亡，并逆转Akt磷酸化和活性的Myc依赖性降低，Akt是Myc诱导细胞凋亡的一种特征良好的抑制因子。我们认为高水平的Myc使Miz 1参与抑制性DNA结合复合物，并抑制支持上皮细胞存活的SRF依赖性转录程序。
Oncogenic levels of Myc expression sensitize cells to multiple apoptotic stimuli, and this protects long‐lived organisms from cancer development. How cells discriminate physiological from supraphysiological levels of Myc is largely unknown. Here, we show that induction of apoptosis by Myc in breast epithelial cells requires association of Myc with Miz1. Gene expression and ChIP‐Sequencing experiments show that high levels of Myc invade target sites that lack consensus E‐boxes in a complex with Miz1 and repress transcription. Myc/Miz1‐repressed genes encode proteins involved in cell adhesion and migration and include several integrins. Promoters of repressed genes are enriched for binding sites of the serum‐response factor (SRF). Restoring SRF activity antagonizes Myc repression of SRF target genes, attenuates Myc‐induced apoptosis, and reverts a Myc‐dependent decrease in Akt phosphorylation and activity, a well‐characterized suppressor of Myc‐induced apoptosis. We propose that high levels of Myc engage Miz1 in repressive DNA binding complexes and suppress an SRF‐dependent transcriptional program that supports survival of epithelial cells.