Recent advances in the structural molecular biology of Ets transcription factors: interactions, interfaces and inhibition

Cooper, C.D.O.; Newman, Joseph A.; Gileadi, O.

doi:10.1042/bst20130227

Cited by 35 publications

(33 citation statements)

References 65 publications

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“…The ETS domain of Ets‐1 has been crystallized in complex with transcription factors GABPαβ and RUNX1 . These structures, as well as homodimers of different proteins of the ETS family (Fev, Elk1, and Etv1), also show the hydrophobic patch to be shielded from the solvent through the interaction with its partners or itself. Moreover, the monomeric structure of ETS (PDB ID: 1GVJ) shows the two inhibitory domains to fold back onto this area, thus protecting the patch from any solvent exposure.…”

Section: Resultsmentioning

confidence: 99%

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

et al. 2018

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The Ets‐1 oncoprotein is a transcription factor that promotes target gene expression in specific biological processes. Typically, Ets‐1 activity is low in healthy cells, but elevated levels of expression have been found in cancerous cells, specifically related to tumor progression. Like the vast majority of the cellular effectors, Ets‐1 does not act alone but in association with partners. Given the important role that is attributed to Ets‐1 in major human diseases, it is crucial to identify its partners and characterize their interactions. In this context, two DNA‐repair enzymes, PARP‐1 and DNA‐PK, have been identified recently as interaction partners of Ets‐1. We here identify their binding mode by means of protein docking. The results identify the interacting surface between Ets‐1 and the two DNA‐repair enzymes centered on the α‐helix H1 of the ETS domain, leaving α‐helix H3 available to bind DNA. The models highlight a hydrophobic patch on Ets‐1 at the center of the interaction interface that includes three tryptophans (Trp338, Trp356, and Trp361). We rationalize the binding mode using a series of computational analyses, including alanine scanning, molecular dynamics simulation, and residue centrality analysis. Our study constitutes a first but important step in the characterization, at the molecular level, of the interaction between an oncoprotein and DNA‐repair enzymes.

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Section: Resultsmentioning

confidence: 99%

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

et al. 2018

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“…5, 6, 7, 8 All ETS factors are characterized by the ETS domain, which is a highly conserved DNA-binding domain comprising ~85 amino acids that form the winged helix-turn-helix DNA-binding motif, and recognizes the core consensus DNA sequence 5′-GGA(A/T)-3′ (ETS-binding site, EBS). 9, 10 Some of them have been found to alter expression patterns involving diverse mechanisms, such as gene fusion and chromosomal rearrangements, 11, 12 amplification and/or overexpression, 13, 14 point mutations.…”

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confidence: 99%

Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

Shi

et al. 2016

Cell Death Dis

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The biological function of E26 transformation-specific (ETS) transcription factor EHF/ESE-3 in human cancers remains largely unknown, particularly gastric cancer. The aim of this study was to explore the role of EHF in tumorigenesis and its potential as a therapeutic target in gastric cancer. By using quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, we investigated the expression and copy number of EHF in a cohort of gastric cancers and control subjects. Specific EHF siRNAs was used to determine the biologic impacts and mechanisms of altered EHF expression in vitro and in vivo. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) assays were performed to identify its downstream targets. Our results demonstrated that EHF was significantly upregulated and frequently amplified in gastric cancer tissues as compared with control subjects. Moreover, EHF amplification was positively correlated with its overexpression and significantly associated with poor clinical outcomes of gastric cancer patients. We also found that EHF knockdown notably inhibited gastric cancer cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice and induced cell cycle arrest and apoptosis. Importantly, we identified EHF as a new HER2 transcription factor and the modulator of HER3 and HER4 in gastric cancer. Collectively, our findings suggest that EHF is a novel functional oncogene in gastric cancer by regulating the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases and may represent a potential prognostic marker and therapeutic target for this cancer.

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“…For instance, Lim et al revealed co-localization with liverspecific TF-binding sites, explaining part of GR's liver cell-specific binding profiles [84]. The molecular mode of regulation at composite sites still remains to be elucidated, although it was hypothesized to fit a model in which only the co-association of the involved TFs results in productive DNA binding, as seen for classical heterodimeric TFs [85,86].…”

Section: Gr-binding Site Sequences and Gr-mediated Transrepressionmentioning

confidence: 99%

Twenty-First Century Glucocorticoid Receptor Molecular Biology

Wang¹,

Oldenkamp²,

Oellers³

et al. 2018

Corticosteroids

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Glucocorticoids are central to homeostasis as a function of the circadian cycle, temporally preceding circulating adrenaline concentration circadian fluctuations. Virtually, all cell types express the glucocorticoid receptor (GR). GR is a transcription factor that activates gene expression by binding to enhancers. Intriguingly, not all cell types respond to GR stimulation in the same fashion at the molecular level. This indicates that GR activity is subject to epigenetic control. We discuss the molecular basis for epigenetic control of GR action at the genomic level, including the concept of topologically associating domains which may restrain the roaming range of distal enhancers. Furthermore, much evidence indicates that GR can repress gene expression programs. We therefore discuss current concepts of the molecular basis of GR-mediated gene expression repression, including non-genomic mechanisms that involve mRNA destabilization.

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Recent advances in the structural molecular biology of Ets transcription factors: interactions, interfaces and inhibition

Cited by 35 publications

References 65 publications

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

Twenty-First Century Glucocorticoid Receptor Molecular Biology

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