Repression of SRF target genes is critical for M yc‐dependent apoptosis of epithelial cells

Autor: Richard Treisman, Bjoern von Eyss, Cyril Esnault, Andreas Rosenwald, Elmar Wolf, Heidi M. Haikala, Martin Eilers, Katrin E. Wiese, Juha Klefström
Přispěvatelé: Lincoln's Inn Fields Laboratories, Cancer Research UK
Rok vydání: 2015
Předmět:
Serum Response Factor
MESH: Cell Line
Tumor
Transcription
Genetic
[SDV]Life Sciences [q-bio]
Kruppel-Like Transcription Factors
Miz1
Myc
Biology
MESH: Mammary Glands
Human
General Biochemistry
Genetics and Molecular Biology
MESH: Cell Adhesion
Proto-Oncogene Proteins c-myc
Cell Movement
Cell Line
Tumor
Serum response factor
Gene expression
Cell Adhesion
MESH: Proto-Oncogene Proteins c-myc
Humans
Mammary Glands
Human
Cell adhesion
MESH: Cell Movement
Molecular Biology
Protein kinase B
Psychological repression
MESH: Humans
General Immunology and Microbiology
MESH: Proto-Oncogene Proteins c-akt
Akt
MESH: Apoptosis
MESH: Transcription
Genetic
General Neuroscience
apoptosis
Epithelial Cells
Promoter
Articles
MESH: Serum Response Factor
MESH: Epithelial Cells
Cancer research
Female
MESH: Kruppel-Like Transcription Factors
Signal transduction
Proto-Oncogene Proteins c-akt
MESH: Female
Zdroj: EMBO Journal
EMBO Journal, EMBO Press, 2015, 34 (11), pp.1554-71. ⟨10.15252/embj.201490467⟩
ISSN: 1460-2075
0261-4189
DOI: 10.15252/embj.201490467
Popis: International audience; 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.
Databáze: OpenAIRE
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