Human glutathione S-transferase P1-1 functions as an estrogen receptor alpha signaling modulator

Abstract

Estrogen receptor alpha (ER alpha) plays a crucial role in estrogen-mediated signaling pathways and exerts its action as a nuclear transcription factor. Binding of the ligand-activated ERa to the estrogen response element (ERE) is a central part of ER alpha-associated signal transduction pathways and its aberrant modulation is associated with many disease conditions. Human glutathione S-transferase P1-1 (GSTP) functions as an enzyme in conjugation reactions in drug metabolism and as a regulator of kinase signaling pathways. It is overexpressed in tumors following chemotherapy and has been associated with a poor prognosis in breast cancer. In this study, a novel regulatory function of GSTP has been proposed in which GSTP modulates ERE-mediated ERa signaling events. Ectopic expression of GSTP was able to induce the ERa and ERE-mediated transcriptional activities in ER alpha-positive but GSTP-negative MCF7 human breast cancer cells. This inductive effect of GSTP on the ERE-transcription activity was diminished when the cells express a mutated form of the enzyme or are treated with a GSTP-specific chemical inhibitor. It was found that GSTP inhibited the expression of the receptor interacting protein 140 (RIP140), a negative regulator of ERa transcription, at both mRNA and protein levels. Our study suggests a novel non-enzymatic role of GSTP which plays a significant role in regulating the classical ERa signaling pathways via modification of transcription cofactors such as RIP140. (C) 2014 Elsevier Inc. All rights reserved.