title: Repression of SRF target genes is critical for Myc-dependent apoptosis of epithelial cells.
abstract: 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.
authors.affiliation: Biocenter Theodor Boveri Institute University of Würzburg, Würzburg, Germany.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Wiese
authors.affiliation: Faculty of Medicine, Cancer Cell Circuitry Laboratory, Translational Cancer Biology Research Program and Institute of Biomedicine Biomedicum Helsinki University of Helsinki, Helsinki, Finland.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Haikala
authors.affiliation: Biocenter Theodor Boveri Institute University of Würzburg, Würzburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: von Eyss
authors.affiliation: Biocenter Theodor Boveri Institute University of Würzburg, Würzburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Cancer Research UK London Research Institute Lincoln's Inn Fields Laboratories Transcription Laboratory, London, UK.
authors.forename: Cyril
authors.initials: C
authors.lastname: Esnault
authors.affiliation: Institute of Pathology University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken University of Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Cancer Research UK London Research Institute Lincoln's Inn Fields Laboratories Transcription Laboratory, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Treisman
authors.affiliation: Faculty of Medicine, Cancer Cell Circuitry Laboratory, Translational Cancer Biology Research Program and Institute of Biomedicine Biomedicum Helsinki University of Helsinki, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Klefström
authors.affiliation: Biocenter Theodor Boveri Institute University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken University of Würzburg, Würzburg, Germany martin.eilers@biozentrum.uni-wuerzburg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D026362:Serum Response Factor; C107961:ZBTB17 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Miz1; Myc; apoptosis