XAP2 inhibits glucocorticoid receptor activity in mammalian cells

Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
FEBS letters (Impact Factor: 3.17). 05/2009; 583(9):1493-8. DOI: 10.1016/j.febslet.2009.03.072
Source: PubMed


XAP2 is member of a protein family sharing the TPR protein interaction motif. It displays close homology to the immunophilins FKBP51 and FKBP52 that act via the Hsp90 folding machinery to regulate the glucocorticoid receptor (GR). We show that XAP2 inhibits GR by reducing its responsiveness to hormone in transcriptional activation. The effect of XAP2 on GR requires its interaction with Hsp90 through the TPR motif. The PPIase-like region turned out to be enzymatically inactive. Thus, PPIase activity is not essential for the action of XAP2 on GR, similarly to FKBP51 and FKBP52.

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    • "Immunodetection of proteins by Western blotting was carried out as described [23], [29], [30]. The protein signals from chemiluminescence were digitally documented (Image station 440 CF and 1D image analysis software 3.6, both from Kodak, USA). "
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    ABSTRACT: Hsp70 binding protein 1 (HspBP1) and Bcl2-associated athanogene 1 (BAG-1), the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70) chaperones, catalyze the release of ADP from Hsp70 while inducing different conformational changes of the ATPase domain of Hsp70. An appropriate exchange rate of ADP/ATP is crucial for chaperone-dependent protein folding processes. Among Hsp70 client proteins are steroid receptors such as the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the androgen receptor (AR). BAG-1 diversely affects steroid receptor activity, while to date the influence of HspBP1 on steroid receptor function is mostly unknown. Here, we compared the influence of HspBP1 and BAG-1M on Hsp70-mediated steroid receptor folding complexes and steroid receptor activity. Coimmunoprecipitation studies indicated preferential binding of Hsp40 and the steroid receptors to BAG-1M as compared to HspBP1. Furthermore, Hsp70 binding to the ligand-binding domain of GR was reduced in the presence of HspBP1 but not in the presence of BAG-1M as shown by pull-down assays. Reporter gene experiments revealed an inhibitory effect on GR, MR, and AR at a wide range of HspBP1 protein levels and at hormone concentrations at or approaching saturation. BAG-1M exhibited a transition from stimulatory effects at low BAG-1M levels to inhibitory effects at higher BAG-1M levels. Overall, BAG-1M and HspBP1 had differential impacts on the dynamic composition of steroid receptor folding complexes and on receptor function with important implications for steroid receptor physiology.
    PLoS ONE 01/2014; 9(1):e85415. DOI:10.1371/journal.pone.0085415 · 3.23 Impact Factor
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    • "Several lines of evidence suggest that AhR is able to mediate offtarget or non-DNA binding dependent transcription . The potential role of AIP in the endocrine disrupting effects of AhR is unclear, but AIP itself has been reported to interfere with steroid receptor activity – i.e. inhibition of glucocorticoid receptor activity through direct AIP/GR/ Hsp90 interaction (Laenger et al. 2009 ) -, further enhancing the complexity of endocrine modulation by the AIP/AhR system. "
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    ABSTRACT: Pituitary adenomas (PA) are common endo-crine neoplasia, generally presenting as sporadic diseases, with a multifactorial pathogenesis including somatic mutational events in cancer-related genes. However, genetic predisposition can currently be recognized in >5% of affected patients, mostly involving the Multiple Endocrine Neoplasia type 1 (MEN1) gene and the more recently identi fi ed Aryl hydrocarbon receptor Interacting Protein (AIP) gene, both being tumor-suppressor genes. Germline mutations in the AIP gene can be observed in a FIPA (Familial Isolated Pituitary Adenoma) context, but also in a minority of young patients with an apparently sporadic disease. Although the role of AIP in the pathogenesis of PA remains largely unknown, it is known to be mainly expressed by somatototrophs, with a frequent loss of expression in most AIP-mutated PA and in invasive somatotro-pinomas. The best characterized function of AIP is to stabilize the Aryl hydrocarbon Receptor, also known as the dioxin receptor, in the cytoplasm, but multiple interactions of AIP with other proteins involved in endo-crine signalling and the regulation of cell cycle and apoptosis have been reported. In this chapter, current knowledge about the possible role of AhR and additional AIP-related proteins in pituitary tumorigenesis will be analysed.
    Tumours of the Central nervous System, Vol 10, Edited by Hayat A.M., 01/2013: chapter The Role of Aryl Hydrocarbon Receptor (AHR) and AHR-Interacting Protein (AIP) in the Pathogenesis of Pituitary Adenomas: pages 189-201; Springer Science+Business Media Dordrecht 2013., ISBN: 978-94-007-5681-6
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    • "Later, XAP2 was identified as an Hsp90-associated protein that specifically interacts with the aryl hydrocarbon receptor (AhR) and regulates both AhR intracellular localization [7] and protein stability by inhibiting AhR ubiquitination [8], [9], [10]. Additional studies, however, have expanded the range of XAP2 client proteins to include also signal transduction proteins like Ga13 [11] and nuclear receptor (NR) superfamily of transcription factors like GR [12], TRβ1 [13] and PPARα [14]. "
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    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.
    PLoS ONE 10/2011; 6(10):e25201. DOI:10.1371/journal.pone.0025201 · 3.23 Impact Factor
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