When Ets transcription factors meet their partners.
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.
Article: ETS transcription factor expression and conversion during prostate and breast cancer progression[show abstract] [hide abstract]
ABSTRACT: ETS factors are known to act as positive or negative regulators of the expression of genes including those that control response to various signaling cascades, cellular proliferation, differentiation, hematopoiesis, apoptosis, adhesion, migration, invasion and metastasis, tissue remodeling, ECM composition and angiogenesis. During cancer progression, altered ETS gene expression disrupts the regulated control of many of these biological processes. Although it was originally observed that specific ETS factors function either as positive or negative regulators of transcription, it is now evident that the same ETS factor may function in reciprocal fashions, reflecting promoter and cell context specificities. This report will present a discussion of ETS factor expression during prostate and breast cancer progression and its functional roles in epithelial cell phenotypes. The ETS genes encode transcription factors that have independent activities but are likely to be part of an integrated network. While previous studies have focused on single ETS factors in the context of specific promoters, future studies should consider the functional impact of multiple ETS present within a specific cell type. The pattern of ETS expression within a single tissue is, not surprisingly, quite complex. Multiple ETS factors may be able to regulate the same genes, albeit at different magnitude or in different directions. Furthermore, the precise balance between cancer promotion and inhibition by ETS factors, which may differentially regulate specific target genes, can thus control its progression. These concepts form the basis of the hypothesis that "Ets conversion" plays a critical role during tumor progression. Examples supporting this hypothesis will be described.The Open Cancer Journal. 01/2010; 3:24-39.
Article: High-dose siRNAs upregulate mouse Eri-1 at both transcription and posttranscription levels.[show abstract] [hide abstract]
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
Article: Molecular dynamics simulations and in silico peptide ligand screening of the Elk-1 ETS domain.[show abstract] [hide abstract]
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