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

2014 ◽  
Vol 42 (1) ◽  
pp. 130-138 ◽  
Author(s):  
Christopher D.O. Cooper ◽  
Joseph A. Newman ◽  
Opher Gileadi
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Protein Interaction ◽  
Eukaryotic Transcription ◽  
Ets Transcription Factors ◽  
Recent Advances ◽  
Ets Family ◽  
Structural Mechanisms ◽  
Ets Factors ◽  
Binding Mechanisms

The Ets family of eukaryotic transcription factors is based around the conserved Ets DNA-binding domain. Although their DNA-binding selectivity is biochemically and structurally well characterized, structures of homodimeric and ternary complexes point to Ets domains functioning as versatile protein-interaction modules. In the present paper, we review the progress made over the last decade to elucidate the structural mechanisms involved in modulation of DNA binding and protein partner selection during dimerization. We see that Ets domains, although conserved around a core architecture, have evolved to utilize a variety of interaction surfaces and binding mechanisms, reflecting Ets domains as dynamic interfaces for both DNA and protein interaction. Furthermore, we discuss recent advances in drug development for inhibition of Ets factors, and the roles structural biology can play in their future.

Regulation of angiogenesis by ETS transcription factors

2009 ◽  
Vol 37 (6) ◽  
pp. 1248-1253 ◽  
Author(s):  
Anna M. Randi ◽  
Andrea Sperone ◽  
Nicola H. Dryden ◽  
Graeme M. Birdsey
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Transcription ◽  
Target Genes ◽  
Ets Transcription Factors ◽  
Ets Family ◽  
Endothelial Gene Expression ◽  
Ets Factors

Transcription factors of the ETS family are important regulators of endothelial gene expression. Here, we review the evidence that ETS factors regulate angiogenesis and briefly discuss the target genes and pathways involved. Finally, we discuss novel evidence that shows how these transcription factors act in a combinatorial fashion with others, through composite sites that may be crucial in determining endothelial specificity in gene transcription.

scholarly journals Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1

2014 ◽  
Vol 289 (31) ◽  
pp. 21605-21616 ◽  
Author(s):  
Shuo Wang ◽  
Miles H. Linde ◽  
Manoj Munde ◽  
Victor D. Carvalho ◽  
W. David Wilson ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Ets Family ◽  
Site Recognition

Describing Delicate Interactions

2007 ◽  
Vol 2007 (369) ◽  
pp. tw24-tw24
Author(s):  
Valda Vinson
Keyword(s):  
Transcription Factors ◽  
Binding Energy ◽  
Dna Binding ◽  
High Throughput ◽  
Biological Networks ◽  
Full Text ◽  
Systems Approach ◽  
Energy Landscapes ◽  
Eukaryotic Transcription ◽  
Link Type

Quantifying the affinities of interactions in biological networks, particularly transient ones, remains a challenge. Maerkl and Quake describe a high-throughput microfluidic platform that allows the measurement of transient and low-affinity interactions and characterize the DNA binding energy landscapes for four eukaryotic transcription factors. In two cases, the binding specificities were used to predict which genes the transcription factors would bind and likely regulate.S. J. Maerkl, S. R. Quake, A systems approach to measuring the binding energy landscapes of transcription factors. Science315, 233-237 (2007). [Abstract][Full Text]

scholarly journals Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN-FOS at composite DNA sites

2018 ◽  
Author(s):  
Bethany J. Madison ◽  
Kathleen A. Clark ◽  
Niraja Bhachech ◽  
Peter C. Hollenhorst ◽  
Barbara J. Graves ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Dna Binding ◽  
Dna Sequences ◽  
Binding Sites ◽  
Epithelial Cell Line ◽  
Electrostatic Repulsion ◽  
Ets Transcription Factors ◽  
Positively Charged

AbstractMany transcription factors regulate gene expression in a combinatorial fashion often by binding in close proximity on composite cis-regulatory DNA elements. Here we investigate the molecular basis by which ETS transcription factors bind with AP1 transcription factors JUN-FOS at composite DNA-binding sites. The ability to bind to DNA with JUN-FOS correlates with the phenotype of these proteins in prostate cancer: the oncogenic ERG and ETV1/4/5 subfamilies co-occupy ETS-AP1 sites with JUN-FOS in vitro, whereas JUN-FOS robustly inhibits DNA binding by the tumor suppressors EHF and SPDEF. EHF binds to ETS-AP1 DNA with tighter affinity than ERG in the absence of JUN-FOS, which may enable EHF to compete with ERG and JUN-FOS for binding to ETS-AP1 sites. Genome-wide mapping of EHF and ERG binding sites in a prostate epithelial cell line reveal that EHF is preferentially excluded from closely spaced ETS-AP1 DNA sequences. Structural modeling and mutational analyses indicate that adjacent positively-charged surfaces from EHF and JUN-FOS disfavor simultaneous DNA binding due to electrostatic repulsion. The conservation of positively charged residues on the JUN-FOS interface identified ELF1 as an additional ETS factor that exhibits anticooperative DNA binding, and we present evidence that ELF1 is frequently downregulated in prostate cancer. In summary, the divergence of electrostatic features of ETS factors at their JUN-FOS interface enables distinct binding events at ETS-AP1 DNA sequences. We propose that this mechanism can drive unique targeting of ETS transcription factors, thereby facilitating distinct transcriptional programs.

Analysis of the ETS Family Member Genes ERG, ETS2, ETS1 and FLI1 in Acute Myeloid Leukemia (AML) Patients with Normal Cytogenetics: Expression Levels and Impact On Clinical Outcome. A Study of the AMLSG.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1600-1600 ◽  
Author(s):  
Verena I. Gaidzik ◽  
Cailian Wang ◽  
Richard F. Schlenk ◽  
Lars Bullinger ◽  
Peter Paschka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Clinical Outcome ◽  
Treatment Protocols ◽  
Ets Transcription Factors ◽  
Free Survival ◽  
Expression Levels ◽  
Ets Family ◽  
Multivariable Analyses ◽  
Normal Cytogenetics

Abstract Abstract 1600 Poster Board I-626 Background The V-ets erythroblastosis virus E26 (ETS) oncogene family is one of the largest families of transcription factors. ETS transcription factors are characterized by two major functional domains, a transcription domain and an evolutionarily highly conserved DNA-binding domain, also known as ETS domain that mediates binding to purine-rich DNA sequences. Most ETS family proteins are nuclear targets for activation of the Ras-MAP kinase signalling pathway. Therefore, they play a significant role in regulating cellular functions such as cell growth, apoptosis, development and differentiation. ETS transcription factors have been implicated in leukemia by chromosomal rearrangement, and more commonly by gene amplification and/or overexpression. Moreover, overexpression of ERG was shown to be an adverse predictor for clinical outcome in AML with normal cytogenetics (CN). In our recent study on complex karyotype AML, array-CGH (comparative genomic hybridization) analysis identified small genomic amplifications affecting ERG/ETS2 in 21q22 and ETS1/FLI1 in 11q23 in about 10% of the cases. Correlation with global gene expression profiling showed that ERG and ETS2 as well as ETS1 and FLI1 were overexpressed in these cases. Aims: To evaluate expression levels of ERG, ETS2, ETS1 and FLI1 in a large cohort of younger (16 to 60 years of age) adult CN-AML patients (pts) and their impact on clinical outcome. Methods The expression of ERG, ETS2, ETS1 and FLI1 was determined by quantitative real-time reverse transcriptase polymerase chain reaction (qPCR) assay in 343 CN-AML pts who were entered on 3 AMLSG treatment protocols (AMLHD93, AML HD98-A, AMLSG 07-04). ERG, ETS2, ETS1, and FLI1 were dichotomized into two major groups according to their expression levels. The upper quartile was chosen as the cut point and the set of patients with gene expression above were defined as Q4 group. Univariable as well as multivariable regression models were used to evaluate the influence of ERG, ETS2, ETS1 and FLI1 on induction success, event-free, relapse-free and overall survival. Multivariable analyses were stratified for AMLSG treatment protocols. Results Partial correlation analysis revealed positive correlations of expression levels between ETS2 and ERG (ρ=0.45) being the strongest, followed by ERG and FLI1 (ρ=0.4), as well as ETS1 and FLI1 (ρ=0.31). Correlation of ERG, ETS2, ETS1 and FLI1 with white blood count (WBC) revealed a significant association between high gene expression (Q4) and elevated WBC (ERG, p=0.004; ETS2, p=0.002, FLI1 p<0.001), whereas high expression of ETS1 was associated with a significantly lower WBC (p<0.001). Univariable as well as multivariable analyses on induction success revealed high ETS2 as an unfavourable marker (OR, 0.29, p=0.01). In univariable analysis, there was a significantly inferior relapse-free survival (RFS) and overall survival (OS) for high ERG (p=.01; p=.06, respectively) and high ETS2 (p=.002; p=.03, respectively) that was even more pronounced when both ERG Q4 and ETS2 Q4 (ERG Q4 ∩ ETS2 Q4) (p<0.001; p=.001, respectively) were included as one variable and compared with the rest. In multivariable analysis for the endpoints event-free survival (EFS), RFS and OS, a significant effect was found for RFS for ERG Q4 ∩ ETS2 Q4 (p=.002); the only significant variables that consistently appeared in the model were NPM1mut, FLT3-ITDpos and WBC. In subgroup analysis for the genotypes CEBPAmut, NPM1mut/FLT3-ITDneg, and all others (NPM1mut/FLT3-ITDpos, NPM1wt/FLT3-ITDpos, NPM1wt/FLT3-ITDneg) according to the hierarchical model, ERG Q4 was associated with an inferior EFS (p=.04) and OS (p=.03) in the favorable CEBPAmut genotype and became even more significant for the variable ERG Q4 ∩ ETS2 Q4 (EFS, p=.007, RFS, p=.002; OS, p=.06, respectively). For the NPM1mut/FLT3-ITDneg subgroup, again ERG Q4 ∩ ETS2 Q4 was associated with an adverse RFS (p=.04), but not with OS (p=0.07). Conclusions In our study on a large cohort of homogenously treated CN-AML patients, ERG and ETS2 expression were highly correlated. Overexpression of both genes had a significant impact on clinical outcome of CN-AML patients. Moreover, adverse effects of high ERG and high ETS2 expression on prognosis were also shown for the genetic AML subgroups CEBPAmut and NPM1mut/FLT3-ITDneg. Disclosures No relevant conflicts of interest to declare.

scholarly journals Single-molecule dynamics and genome-wide transcriptomics reveal that NF-κB (p65)-DNA binding times can be decoupled from transcriptional activation

2018 ◽  
Author(s):  
Andrea Callegari ◽  
Christian Sieben ◽  
Alexander Benke ◽  
David M. Suter ◽  
Beat Fierz ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Single Molecule ◽  
Protein Interaction ◽  
Transcriptional Activation ◽  
Dna Binding Domain ◽  
Protein Protein Interaction ◽  
Genome Wide ◽  
Binding Time ◽  
Transcriptional Output

AbstractTranscription factors (TFs) regulate gene expression in both prokaryotes and eukaryotes by recognizing and binding to specific DNA promoter sequences. In higher eukaryotes, it remains unclear how the duration of TF binding to DNA relates to downstream transcriptional output. Here, we address this question for the transcriptional activator NF-κB (p65), by live-cell single molecule imaging of TF-DNA binding kinetics and genome-wide quantification of p65-mediated transcription. We used mutants of p65, perturbing either the DNA binding domain (DBD) or the protein-protein transactivation domain (TAD). We found that p65-DNA binding time was predominantly determined by its DBD and directly correlated with its transcriptional output as long as the TAD is intact. Surprisingly, mutation or deletion of the TAD did not modify p65-DNA binding stability, suggesting that the p65 TAD generally contributes neither to the assembly of an “enhanceosome,” nor to the active removal of p65 from putative specific binding sites. However, TAD removal did reduce p65-mediated transcriptional activation, indicating that protein-protein interactions act to translate the long-lived p65-DNA binding into productive transcription.Author SummaryTo control transcription of a certain gene or a group of genes, both eukaryotes and prokaryotes express specialized proteins, transcription factors (TFs). During gene activation, TFs bind gene promotor sequences to recruit the transcriptional machinery including DNA polymerase II. TFs are often multi-subunit proteins containing a DNA-binding domain (DBD) as well as a protein-protein interaction interface. It was suggested that the duration of a TF-DNA binding event 1) depends on these two subunits and 2) dictates the outcome, i.e. the amount of mRNA produced from an activated gene. We set out to address these hypotheses using the transcriptional activator NF-κB (p65) as well as a number of mutants affecting different functional subunits. Using a combination of live-cell microscopy and RNA sequencing, we show that p65 DNA-binding time indeed correlates with the transcriptional output, but that this relationship depends on, and hence can be uncoupled by altering, the protein-protein interaction capacity. Our results suggest that, while p65 DNA binding times are dominated by the DBD, a transcriptional output can only be achieved with a functional protein-protein interaction subunit.

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