Disease relevance of AIP

• Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently identified in individuals with pituitary adenoma predisposition (PAP) [1].
• To examine the possible role of AIP in the genesis of common cancers, we performed somatic mutation screening in a series of 373 colorectal cancers (CRCs), 82 breast cancers, and 44 prostate tumour samples [1].
• Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers [1].
• Epstein-Barr virus encoded nuclear protein EBNA-3 binds XAP-2, a protein associated with Hepatitis B virus X antigen [2].
• PATIENTS: 64 consecutive patients with acute pancreatitis were enrolled in this prospective study; 29 were suffering from acute oedematous pancreatitis (AIP), and 35 from necrotising disease (NP) as diagnosed by contrast enhanced computed tomography [3].

Psychiatry related information on AIP

• In western countries this is associated with the known increase in alcohol consumption and AIP [4].

High impact information on AIP

• In cultured cells, overexpression of AIP enhanced preornithine transcarbamylase import, and depletion of AIP by RNA interference impaired the import [5].
• These results suggest that AIP functions as a cytosolic factor that mediates preprotein import into mitochondria [5].
• First, in the absence of ligand, the dioxin receptor-hsp90 complex was associated with the immunophilin-like protein XAP2 to mediate cytoplasmic retention of the dioxin receptor [6].
• XAP2 enhanced the ability of endogenous murine and human AhR complexes to activate a dioxin-responsive element-luciferase reporter twofold, following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells [7].
• Internal amino acid sequence information was obtained, and p38 was identified as the hepatitis B virus X-associated protein 2 (XAP2) [7].

Chemical compound and disease context of AIP

• Abnormal glucose tolerance occurred in 91% of patients with calcific pancreatitis and 70% of patients with noncalific AIP in our follow up of five to 12 years [4].
• We have shown that pyrimidinone molecule, 2 amino-5-iodo-6-phenyl-4-pyrimidinone (AIPP) after regional administration, displayed both prophylactic and therapeutic effect on ascitic mammary adenocarcinoma, ACA-755 [8].

Biological context of AIP

• Finally, we have characterized the developmental and expression pattern of ARA9 in the developing mouse embryo and mapped the ARA9 locus to human chromosome 11q13.3 [9].
• The C-terminal half of the receptor, containing the transactivation domain, determines the cellular localization of the transiently transfected receptor and regulates the ability of hepatitis B virus X-associated protein 2 (XAP2) to inhibit ligand-independent nuclear import of AhR [10].
• Loss-of-heterozygosity (LOH) analysis revealed that AIP is lost in PAP tumours, suggesting that it acts as a tumour-suppressor gene [1].
• In transfection assays, overexpression of XAP2 abolishes transactivation by the X protein [11].
• Protein kinase CK2 (CK2) was identified as the 45-kDa kinase from COS 1 cell or liver extracts that was responsible for phosphorylation of serine 43 in the XAP2 peptide 39-57 [12].

Anatomical context of AIP

• These mutations resulted in the loss of AhR binding to endogenous XAP2 in COS-1 cells and reduced binding of exogenously expressed XAP2 [13].
• In vitro experiments using proteins generated in reticulocyte lysates confirmed this interaction and indicated that ARA9 can be co-immunoprecipitated with the AHR using antisera raised specifically for either the AHR or the 90-kDa heat shock protein [14].
• Multiple somatotopic representations of the face, lips, and fingers were localized and mapped in primary motor cortex (MI), ventral premotor cortex (PMv), polysensory zone (PZ), primary (SI) and secondary (SII) somatosensory cortex, parietal ventral area (PV) and 7b, as well as anterior and ventral intraparietal areas (AIP and VIP) [15].
• From Northern blot analyses, XAP2 is ubiquitously expressed in both liver-derived and non-liver-derived cell lines as well as in normal non-liver tissues [11].
• Surprisingly, however, we found that AIP still could induce H2O2-independent apoptosis more slowly than H2O2-dependent one in HL-60 cells even in the presence of antioxidants [16].

Associations of AIP with chemical compounds

• In contrast, hAhR-YFP localized predominantly in the cytoplasm, and coexpression of XAP2 did not affect this localization, and did not block nuclear accumulation in the presence of leptomycin B [17].
• Furthermore, all of these serine mutants were able to sequester murine AhR-YFP into the cytoplasm as well as wild-type XAP2 [12].
• These results indicate that AIP induces apoptosis in cells by two distinct mechanisms; one rapid and mediated by H2O2, the other delayed and mediated by deprivation of L-lysine, both of which utilize caspase-9/cytochrome c system [16].
• In this study, we confirmed that recombinant AIP generated enough H2O2 in culture medium to induce rapid apoptosis in cells and this apoptosis was clearly inhibited by co-cultivation with antioxidants such as catalase and N-acetyl-cysteine [16].
• In addition, since non-natriferic concentrations of cortisol did not induce similar proteins, AIP synthesis appears to be mineralocorticoid-specific [18].

Physical interactions of AIP

• Additionally the XAP2 binding-deficient AhR mutants showed overall higher transcriptional activity when compared with the non-mutant receptor [13].
• The ALG-2/AIP-complex, a modulator at the interface between cell proliferation and cell death? A hypothesis [19].

Regulatory relationships of AIP

• XAP2 expression caused an overall repression of constitutive and ligand-induced AhR transcriptional activity [13].
• We have identified the mechanism of XAP-2-induced cytoplasmic localization of the receptor and studied the potential cross-talk between CRM-1 and XAP-2 [20].

Other interactions of AIP

• We and others have demonstrated that XAP2 retains the nonactivated AhR in the cell cytoplasm [21].
• Finally XAP2 itself was capable of existing in multimeric complexes, and these complexes did not require Hsp90 or AhR to form [13].
• One of the ligand-dependent clones, ARA9, encodes a novel 330-amino acid protein with regions of amino acid sequence similarity to the 52-kDa FK506-binding protein known to be associated with the glucocorticoid receptor [14].
• Role of AIP and its homologue the blindness-associated protein AIPL1 in regulating client protein nuclear translocation [22].
• CRM-1-mediated nuclear export occurs independently of XAP-2 [20].

Analytical, diagnostic and therapeutic context of AIP

• Using the yeast two-hybrid method, we have isolated a clone that encodes a novel X-associated cellular protein: XAP2 [11].
• In a proteomics screening to identify novel survivin-binding partners, we found that the aryl hydrocarbon receptor-interacting protein (AIP) directly associates with survivin in vitro and in co-immunoprecipitation experiments in vivo [23].
• Three segments of the AIP gene that contain the reported mutation sites for Q14X, IVS3-1G>A, and R304X were amplified by PCR and sequenced [24].
• Our event related fMRI study was designed to address specifically the question, how CIP and AIP interact in the process of adjustment of hand orientation towards objects [25].
• RESULTS: Patients who were admitted for pleurisy, cancer of the kidney and renal pelvis, or conduction disorders and complications of cardiac devices had the highest rates of developing AIP during hospitalization, with AIP rates at 2.24%, 1.14%, and 0.83% respectively [26].

References