XAP2 inhibits glucocorticoid receptor activity in mammalian cells

Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
FEBS letters (Impact Factor: 3.34). 05/2009; 583(9):1493-8. DOI: 10.1016/j.febslet.2009.03.072
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene have been reported in 15-40% of FIPA patients. Limited data are available on the functional consequences of the mutations or regarding the regulation of the AIP gene. We describe a large cohort of FIPA families and characterize missense and silent mutations using minigene constructs, luciferase and beta-galactosidase assays, as well as in silico predictions. Patients with AIP mutations had a lower mean age at diagnosis (23.6+/-11.2 years) than AIP mutation-negative patients (40.4+/-14.5 years). A promoter mutation showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein-protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In summary, exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in our FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants.
    Human Mutation 08/2010; 31(8):950-60. DOI:10.1002/humu.21292 · 5.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The exposed surface of the eye is continuously covered by a thin film of fluid, the tear film, which covers the entire ocular surface, including the cornea (the clear “window” of the eye) and conjunctiva (the white part of the eye, which extends under the eyelid). The tear film is a complex fluid that is secreted by several different glands surrounding the eye. The epithelial cells of the ocular surface itself also secrete components of the tear film. The action of blinking spreads the film of tears over the whole surface of the eye and mixes the tears underneath the lids. The tear film serves as an interface between the external environment and the ocular surface and is the first layer of protection for the cornea and conjunctiva. It is constantly responding to stresses that include desiccation, bright light, cold, mechanical stimulation, physical injury, noxious chemicals, and bacterial, viral, and parasitic infection. The tear film also maintains the health of the cornea and conjunctiva by providing optimal electrolyte composition, pH, nutrient levels, and a complex mix of proteins, lipids, and mucin. To respond to these various external and internal requirements, exquisite control of the volume, composition, and structure of the tear film is required. This control arises from regulating secretion from the individual orbital glands and ocular surface epithelia. Regulation of tear secretion provides an extremely stable fluid that protects and maintains the cornea and conjunctiva and ensures that the transparent cornea provides the retina with its window to the world and ensures clear vision.


1 Download
Available from