Premium
Repression of SRF target genes is critical for M yc‐dependent apoptosis of epithelial cells
Author(s) -
Wiese Katrin E,
Haikala Heidi M,
Eyss Björn,
Wolf Elmar,
Esnault Cyril,
Rosenwald Andreas,
Treisman Richard,
Klefström Juha,
Eilers Martin
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201490467
Subject(s) - library science , computer science
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 Ch IP ‐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.