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J Mol Biol. 2017 Oct 13;429(20):2975-2995. doi: 10.1016/j.jmb.2017.06.024. Epub 2017 Jul 17.

ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain.

Author information

1
Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, 84112-5500, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112-5500, USA.
2
Departments of Biochemistry and Molecular Biology, Department of Chemistry, and Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
3
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112-5650, USA.
4
Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, 84112-5500, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112-5500, USA; Howard Hughes Medical Institute, Chevy Chase, MD, 20815-6789, USA. Electronic address: Barbara.Graves@utah.edu.

Abstract

The recruitment of transcriptional cofactors by sequence-specific transcription factors challenges the basis of high affinity and selective interactions. Extending previous studies that the N-terminal activation domain (AD) of ETV5 interacts with Mediator subunit 25 (MED25), we establish that similar, aromatic-rich motifs located both in the AD and in the DNA-binding domain (DBD) of the related ETS factor ETV4 interact with MED25. These ETV4 regions bind MED25 independently, display distinct kinetics, and combine to contribute to a high-affinity interaction of full-length ETV4 with MED25. High-affinity interactions with MED25 are specific for the ETV1/4/5 subfamily as other ETS factors display weaker binding. The AD binds to a single site on MED25 and the DBD interacts with three MED25 sites, allowing for simultaneous binding of both domains in full-length ETV4. MED25 also stimulates the in vitro DNA binding activity of ETV4 by relieving autoinhibition. ETV1/4/5 factors are often overexpressed in prostate cancer and genome-wide studies in a prostate cancer cell line indicate that ETV4 and MED25 occupy enhancers that are enriched for ETS-binding sequences and are both functionally important for the transcription of genes regulated by these enhancers. AP1-motifs, which bind JUN and FOS transcription factor families, were observed in MED25-occupied regions and JUN/FOS also contact MED25; FOS strongly binds to the same MED25 site as ETV4 AD and JUN interacts with the other two MED25 sites. In summary, we describe features of the multivalent ETV4- and AP1-MED25 interactions, thereby implicating these factors in the recruitment of MED25 to transcriptional control elements.

KEYWORDS:

ETS transcription factors; JUN/FOS.; Mediator complex.; Prostate cancer.

PMID:
28728983
PMCID:
PMC5632138
DOI:
10.1016/j.jmb.2017.06.024
[Indexed for MEDLINE]
Free PMC Article

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