Article

When Ets transcription factors meet their partners.

CNRS UMR 8526, Institut de Biologie de Lille, B.P. 447, 1 rue Calmette, 59021 Lille Cedex, France.
BioEssays (impact factor: 4.95). 05/2002; 24(4):362-70. DOI:10.1002/bies.10068 pp.362-70
Source: PubMed

ABSTRACT Ets proteins are a family of transcription factors that regulate the expression of a myriad of genes in a variety of tissues and cell types. This functional versatility emerges from their interactions with other structurally unrelated transcription factors. Indeed, combinatorial control is a characteristic property of Ets family members, involving interactions between Ets and other key transcriptional factors such as AP1, SRF, and Pax family members. Intriguingly, recent molecular modeling and crystallographic data suggest that not only the ETS DNA-binding domain, but also the DNA recognition helix alpha3, are often directly required for Ets partner's selection. Indeed, while most DNA-binding proteins appear to exploit differences within their DNA recognition helices for sites selection, the Ets proteins exploit differences in their surfaces that interact with other transcription factors, which in turn may modify their DNA-binding properties in a promoter-specific fashion. Taken together, the gene-specific architecture of these unique complexes can mediate the selective control of transcriptional activity.

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    Dennis K Watson, David P Turner, Melissa N Scheiber, Victoria J Findlay, Patricia M Watson
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    Article: High-dose siRNAs upregulate mouse Eri-1 at both transcription and posttranscription levels.
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    ABSTRACT: The eri-1 gene encodes a 3' exonuclease that can negatively regulate RNA interference via siRNase activity. High-dose siRNAs (hd-siRNAs) can enhance Eri-1 expression, which in return degrade siRNAs and greatly reduces RNAi efficiency. Here we report that hd-siRNAs induce mouse Eri-1 (meri-1) expression through the recruitment of Sp1, Ets-1, and STAT3 to the meri-1 promoter and the formation of an Sp1-Ets-1-STAT3 complex. In addition, hd-siRNAs also abolish the 3' untranslated region (UTR) mediated posttranscriptional repression of meri-1. Our findings demonstrate the molecular mechanism underlying the upregulation of meri-1 by hd-siRNA.
    PLoS ONE 01/2011; 6(10):e26466. · 4.09 Impact Factor
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    Article: Molecular dynamics simulations and in silico peptide ligand screening of the Elk-1 ETS domain.
    Abrar Hussain, Peter E Shaw, Jonathan D Hirst
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    ABSTRACT: The Elk-1 transcription factor is a member of a group of proteins called ternary complex factors, which serve as a paradigm for gene regulation in response to extracellular signals. Its deregulation has been linked to multiple human diseases including the development of tumours. The work herein aims to inform the design of potential peptidomimetic compounds that can inhibit the formation of the Elk-1 dimer, which is key to Elk-1 stability. We have conducted molecular dynamics simulations of the Elk-1 ETS domain followed by virtual screening. We show the ETS dimerisation site undergoes conformational reorganisation at the α1β1 loop. Through exhaustive screening of di- and tri-peptide libraries against a collection of ETS domain conformations representing the dynamics of the loop, we identified a series of potential binders for the Elk-1 dimer interface. The di-peptides showed no particular preference toward the binding site; however, the tri-peptides made specific interactions with residues: Glu17, Gln18 and Arg49 that are pivotal to the dimer interface. We have shown molecular dynamics simulations can be combined with virtual peptide screening to obtain an exhaustive docking protocol that incorporates dynamic fluctuations in a receptor. Based on our findings, we suggest experimental binding studies to be performed on the 12 SILE ranked tri-peptides as possible compounds for the design of inhibitors of Elk-1 dimerisation. It would also be reasonable to consider the score-ranked tri-peptides as a comparative test to establish whether peptide size is a determinant factor of binding to the ETS domain.
    Journal of Cheminformatics 11/2011; 3(1):49. · 3.42 Impact Factor

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Keywords

cell types
 
characteristic property
 
crystallographic data
 
DNA recognition helix alpha3
 
DNA-binding properties
 
DNA-binding proteins
 
ETS DNA-binding domain
 
Ets family members
 
Ets proteins
 
functional versatility
 
gene-specific architecture
 
key transcriptional factors
 
Pax family members
 
promoter-specific fashion
 
recent molecular modeling
 
sites selection
 
structurally unrelated transcription factors
 
transcription factors
 
transcriptional activity
 
unique complexes