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

Estrogen receptor α (ERα), as a ligand-dependent transcription factor, mediates 17β-estra-diol (E2) effects. ERα is a modular protein containing a DNA binding domain (DBD) and transcription activation domains (AD) located at the amino- and carboxyl-termini. The inter-action of the E2-activated ERα dimer with estrogen response elements (EREs) of genes constitutes the initial step in the ERE-dependent signaling pathway necessary for alter-ations of cellular features. We previously constructed monomeric transcription activators, or monotransactivators, assembled from an engineered ERE-binding module (EBM) using the ERα-DBD and constitutively active ADs from other transcription factors. Monotransactiva-tors modulated cell proliferation by activating and repressing ERE-driven gene expressions that simulate responses observed with E2-ERα. 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-ERα or monotransactivators. Consistent with this, monotransre-pressors suppressed reporter gene expressions that emulate the ERE-dependent signalin