Repression of SRF target genes is critical for Myc-dependent apoptosis of epithelial cells

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.

Keywords: Akt; Miz1; Myc; apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Cell Adhesion / physiology
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Female
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Serum Response Factor / genetics
  • Serum Response Factor / metabolism*
  • Transcription, Genetic / physiology*


  • Kruppel-Like Transcription Factors
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Serum Response Factor
  • ZBTB17 protein, human
  • Proto-Oncogene Proteins c-akt