Date

2015-08-21

Author

Muyan, Mesut
Yasar, Pelin
Ayaz, Gamze
User, Sirma Damla
Kazan, Hasan Huseyin
Huang, Yanfang

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Estrogen receptor a (ER alpha), as a ligand-dependent transcription factor, mediates 17 beta-estradiol (E2) effects. ERa 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 ERa 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.

Subject Keywords

HUMAN-BREAST-CANCER, ZINC-FINGER PROTEINS, RECEPTOR-ALPHA, ER-ALPHA, ACTIVATION FUNCTIONS, REPRESSION, ESTRADIOL, BINDING, DOMAIN, CELLS

URI

https://hdl.handle.net/11511/37786

Collections

Department of Biology, Article