The Immunophilin-Like Protein XAP2 Is a Negative Regulator of Estrogen Signaling through Interaction with Estrogen Receptor α

Wen Cai,Petra Berg,Ingemar Pongratz,Marta Korbonits,Tatiana V Kramarova,Susan Kovats

doi:10.1371/journal.pone.0025201

Abstract

XAP2 (also known as aryl hydrocarbon receptor interacting protein, AIP) is originally identified as a negative regulator of the hepatitis B virus X-associated protein. Recent studies have expanded the range of XAP2 client proteins to include the nuclear receptor family of transcription factors. In this study, we show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. Interestingly, we show that XAP2 downregulates the E2-dependent transcriptional activation in an estrogen receptor (ER) isoform-specific manner: XAP2 inhibits ERα but not ERβ-mediated transcription. Thus, knockdown of intracellular XAP2 levels leads to increased ERα activity. XAP2 proteins, carrying mutations in their primary structures, loose the ability of interacting with ERα and can no longer regulate ER target gene transcription. Taken together, this study shows that XAP2 exerts a negative effect on ERα transcriptional activity and may thus prevent ERα-dependent events.

Highlights

The Hepatitis B virus X protein associated protein 2 (XAP2) is a 37 kD immunophilin-like factor known as aryl hydrocarbon receptor-associated protein 9 (ARA9) or aryl hydrocarbon receptor-interacting protein (AIP) [1,2,3]
We have investigated the role of XAP2 in regulation of E2-dependent transcriptional activation
XAP2 was originally identified as a negative regulator of the hepatitis B virus X-associated protein [5], and it has been shown to protect aryl hydrocarbon receptor (AhR) from protein degradation by inhibiting AhR ubiquitination [9]

Summary

Introduction

The Hepatitis B virus X protein associated protein 2 (XAP2) is a 37 kD immunophilin-like factor known as aryl hydrocarbon receptor-associated protein 9 (ARA9) or aryl hydrocarbon receptor-interacting protein (AIP) [1,2,3]. Estrogen signaling is involved in variety of physiological processes, both in females and males, in both reproductive and non-reproductive tissues [17,18] Both ERa and ERb are the mediators of the effects of estrogen, they have distinct, or even opposing effects in certain tissues where the biological action of estrogen ligands depends on a balance between ERa and ERb [19,20]. Several studies have demonstrated that the tumorigenic effects of estrogens are primarily mediated by ERa. Lifetime exposure and high estrogen levels and high ER transcriptional activity represent a risk factor for developing tumors in breast [21], endometrial [22], ovarian [23] pituitary [24] and thyroid tissues [25]. Our experiments demonstrate that XAP2 is a negative regulator of ERa transcriptional activity and expand the list of XAP2 client proteins to include ERa

Materials and Methods

Findings

Discussion