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

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.

Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations

“…A similar nonsignificant trend was present in our series (data not shown), but the higher proportion of female cases could have introduced some bias and no gender specificity could be shown. However, the unusual male predominance in AIP mut somatotropinomas and reported interactions between AIP, AHR and steroid receptors (Beischlag et al 2008), in particular oestrogen receptor a (Matthews & Gustafsson 2006, Cai et al 2011, suggest potential variations in AIP expression or function according to patient's gender and the steroid milieu, which deserve further investigation. Because the cyclin kinase inhibitor p27 Kip1 can be induced by SSA (Ferrante et al 2006) and by AHR signalling (Marlowe & Puga 2005), we proposed the hypothesis that AHR itself could be a target of SSA in GH-PA.…”

Functions of the Hsp90-Binding FKBP Immunophilins

“…As the name implies, Xap2 also functionally interacts with the hepatitis B virus protein X (Kuzhandaivelu et al 1996). Recently, Xap2 was shown to exert an inhibitory effect on both GR and ERα, but not ERβ activity, and may inhibit AR and PR as well (Cai et al 2011;Laenger et al 2009;Schulke et al 2010). In addition, Xap2 is known to have functional interactions with peroxisome proliferator activated receptor α (PPARα) (Sumanasekera et al 2003) and thyroid hormone receptor β, however, these interactions have not been extensively characterized.…”

GREB1 (growth regulation by estrogen in breast cancer 1)

“…In addition, ChIP analysis revealed the binding of ERα, the steroid receptor coactivator-3, acetylated histones and phosphorylated RNA polymerase II to all three EREs in the presence of E 2 (Deschênes et al, 2007). Subsequently, GREB-1 is now a well characterised estrogen responsive gene used to identify ERα activity (Cai et al, 2011;Chand et al, 2012;Gupta et al, 2012;Liu et al, 2012;Rae et al, 2005;Sun et al, 2007;Woodfield et al, 2010). Hnatyszyn, et al developed a novel GREB-1 antibody which was used to detect GREB-1 protein expression in ERα +ve breast cancer cells and tissue (Hnatyszyn et al, 2010).…”