Modulation of Estrogen Response Element-Driven Gene Expressions and Cellular Proliferation with Polar Directions by Designer Transcription Regulators: e0136423

Estrogen receptor alpha (ER alpha ), as a ligand-dependent transcription factor, mediates 17[Beta]-estradiol (E2) effects. ER alpha is a modular protein containing a DNA binding domain (DBD) and transcription activation domains (AD) located at the amino- and carboxyl-termini. The interaction of the...

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Veröffentlicht in:PloS one 2015-08, Vol.10 (8)
Hauptverfasser: Muyan, Mesut, Guepuer, Gizem, Yasar, Pelin, Ayaz, Gamze, User, Sirma Damla, Kazan, Hasan Hueseyin, Huang, Yanfang
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Sprache:eng
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Zusammenfassung:Estrogen receptor alpha (ER alpha ), as a ligand-dependent transcription factor, mediates 17[Beta]-estradiol (E2) effects. ER alpha is a modular protein containing a DNA binding domain (DBD) and transcription activation domains (AD) located at the amino- and carboxyl-termini. The interaction of the E2-activated ER alpha dimer with estrogen response elements (EREs) of genes constitutes the initial step in the ERE-dependent signaling pathway necessary for alterations of cellular features. We previously constructed monomeric transcription activators, or monotransactivators, assembled from an engineered ERE-binding module (EBM) using the ER alpha -DBD and constitutively active ADs from other transcription factors. Monotransactivators modulated cell proliferation by activating and repressing ERE-driven gene expressions that simulate responses observed with E2-ER alpha . We reasoned here that integration of potent heterologous repression domains (RDs) into EBM could generate monotransrepressors that alter ERE-bearing gene expressions and cellular proliferation in directions opposite to those observed with E2-ER alpha or monotransactivators. Consistent with this, monotransrepressors suppressed reporter gene expressions that emulate the ERE-dependent signaling pathway. Moreover, a model monotransrepressor regulated DNA synthesis, cell cycle progression and proliferation of recombinant adenovirus infected ER-negative cells through decreasing as well as increasing gene expressions with polar directions compared with E2-ER alpha or monotransactivator. Our results indicate that an 'activator' or a 'repressor' possesses both transcription activating/enhancing and repressing/decreasing abilities within a chromatin context. Offering a protein engineering platform to alter signal pathway-specific gene expressions and cell growth, our approach could also be used for the development of tools for epigenetic modifications and for clinical interventions wherein multigenic de-regulations are an issue.
ISSN:1932-6203
DOI:10.1371/journal.pone.0136423