Wiese Katrin E, Haikala Heidi M, von Eyss Björn, Wolf Elmar, Esnault Cyril, Rosenwald Andreas, Treisman Richard, Klefström Juha, Eilers Martin
Biocenter Theodor Boveri Institute University of Würzburg, Würzburg, Germany.
Faculty of Medicine, Cancer Cell Circuitry Laboratory, Translational Cancer Biology Research Program and Institute of Biomedicine Biomedicum Helsinki University of Helsinki, Helsinki, Finland.
EMBO J. 2015 Jun 3;34(11):1554-71. doi: 10.15252/embj.201490467. Epub 2015 Apr 20.
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.
致癌水平的Myc表达使细胞对多种凋亡刺激敏感，这保护长寿生物体免受癌症发展。细胞如何区分生理水平和超生理水平的Myc在很大程度上尚不清楚。在这里，我们表明Myc在乳腺上皮细胞中诱导凋亡需要Myc与Miz1结合。基因表达和染色质免疫沉淀测序实验表明，高水平的Myc与Miz1形成复合物侵入缺乏共有E-box的靶位点并抑制转录。Myc/Miz1抑制的基因编码参与细胞粘附和迁移的蛋白质，包括几种整合素。被抑制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诱导的凋亡，并逆转Myc依赖性的Akt磷酸化和活性降低，Akt是Myc诱导凋亡的一种特征明确的抑制剂。我们提出，高水平的Myc使Miz1参与抑制性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。
