AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE37927 | GEO | 2014/03/05
SECONDARY ACCESSION(S): PRJNA165687
REPOSITORIES: GEO
Similar Datasets
Project description:Gene-level expression profiles of 7 Aip knock-out (triplicates from each) and 9 Aip wild-type mouse embryonic fibroblast cell lines were studied using Affymetrix GeneChip Mouse Exon 1.0 ST Arrays All samples were quantile-normalized by the RMA method (Robust Multichip Average) using re-mapped gene annotations from Brainarray Custom CDF files (MoEx10stv1, Version 14.1.0, http://brainarray.mbni.med.umich.edu/Brainarray/default.asp). A 2-way ANOVA was constructed to identify genes that differentially expressed between KO and WT samples. False discovery rate control (FDR) with Benjamini and Hochberg method was used to correct for multiple testing
2014-03-05 | E-GEOD-37927 | biostudies-arrayexpress
Project description:The aim of this study was to perform comparative gene expression analysis of AIP mutation-positive, AIP mutation-negative familial and sporadic somatotroph tumours to discover the genes/pathways responsible for the aggressive phenotype. Gene expression analysis was performed on 25 pituitary samples (five normal pituitary, six AIPpos GH, three AIPneg GH, four sporadic GH, two AIPneg familial NFPA and five sporadic NFPA adenomas) using the Affymetrix human Gene Chip HG-U133 Plus 2.0 array.
2018-04-13 | GSE63357 | GEO
Project description:PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and therefore regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary but was significantly overexpressed in somatotroph, lactotroph, corticotroph and clinically nonfunctioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly overexpressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse two-hybrid screen identified numerous additional variants in the tetratricopeptide repeat (TPR) region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis.
| S-EPMC4901527 | biostudies-literature
Project description:Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germline AIP mutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigate the role of miRNA dysregulation in AIPmut+ versus AIPmut- PA samples by array analysis. miR-34a and miR-145 were found highly expressed in AIPmut+ vs AIPmut-somatotropinomas. Ectopic expression of AIPmut (p.R271W) in Aip-/- mouse embryonic fibroblasts upregulated miR-34a and miR-145, establishing a causal link between AIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and anti-proliferative effects. miR-34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIPmut+ versus AIPmut- PA. Taken together, somatotropinomas with AIP mutations overexpress miR-34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut+ acromegaly.
2020-08-18 | GSE140604 | GEO
Project description:Human brown fat tumors (hibernomas) display concomitant loss of the tumor suppressor genes MEN1 and AIP. In the present study, we hypothesized that the brown fat phenotype is attributed to these mutations. Accordingly, we demonstrate that silencing of AIP in human brown preadipocytic and white fat cell lines results in the induction of the brown fat marker UCP1. In human adipocytic tumors, loss of MEN1 was found both in white (one out of 51 lipomas) and brown fat tumors. In contrast, concurrent loss of AIP was always accompanied by a brown fat morphology. We conclude that this white-to-brown phenotype switch in brown fat tumors is mediated by the loss of AIP.
2017-08-10 | GSE61093 | GEO
Project description:Comparison of genes associated with the EMT between cytotrophoblast cells (CTB) and extravillous trophoblast cells (EVT) from normal third trimester placenta and abnormally invasive placenta (AIP)
2018-01-01 | GSE104350 | GEO
Project description:Hibernomas are benign tumors with morphological features resembling brown fat. They consistently display cytogenetic rearrangements, typically translocations, involving chromosome band 11q13. Here we demonstrate that these aberrations are associated with concomitant deletions of AIP and MEN1, tumor suppressor genes that are located 3 Mb apart and that underlie the hereditary syndromes pituitary adenoma predisposition and multiple endocrine neoplasia type I. MEN1 and AIP displayed a low expression in hibernomas whereas the expression of genes up-regulated in brown fat-PPARA, PPARG, PPARGC1A, and UCP1-was high. Thus, loss of MEN1 and AIP is likely to be pathogenetically essential for hibernoma development. Simultaneous loss of two tumor suppressor genes has not previously been shown to result from a neoplasia-associated translocation. Furthermore, in contrast to the prevailing assumption that benign tumors harbor relatively few genetic aberrations, the present analyses demonstrate that a considerable number of chromosome breaks are involved in the pathogenesis of hibernoma.
2010-11-24 | GSE19040 | GEO
Project description:BackgroundPituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy.AimsWe performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center.MethodsPituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response.ResultsFifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen.ConclusionsGermline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients.
| S-EPMC6432872 | biostudies-literature
Project description:Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been shown to predispose to pituitary adenoma predisposition, a condition characterized by growth hormone (GH)-secreting pituitary tumors. To study AIP-mediated tumorigenesis, we generated an Aip mouse model. Heterozygous mice developed normally but were prone to pituitary adenomas, in particular to those secreting GH. A complete loss of AIP was detected in these lesions, and full penetrance was reached at the age of 15 months. No excess of any other tumor type was found. Ki-67 analysis indicated that Aip-deficient tumors have higher proliferation rates compared with Aip-proficient tumors, suggesting a more aggressive disease. Similar to human AIP-deficient pituitary adenomas, immunohistochemical studies showed that expression of aryl hydrocarbon receptor nuclear translocator 1 or 2 (ARNT or ARNT2) protein was lost in the mouse tumors, suggesting that mechanisms of AIP-related tumorigenesis involve aberrant ARNT function. The Aip(+/-) mouse appears to be an excellent model for the respective human disease phenotype. This model constitutes a tool to further study AIP-associated pituitary tumorigenesis and may be potentially valuable in efforts to develop therapeutic strategies to treat pituitary adenomas.
| S-EPMC2947291 | biostudies-literature
Project description:Hibernomas are benign tumors with morphological features resembling brown fat. They consistently display cytogenetic rearrangements, typically translocations, involving chromosome band 11q13. Here we demonstrate that these aberrations are associated with concomitant deletions of AIP and MEN1, tumor suppressor genes that are located 3 Mb apart and that underlie the hereditary syndromes pituitary adenoma predisposition and multiple endocrine neoplasia type I. MEN1 and AIP displayed a low expression in hibernomas whereas the expression of genes up-regulated in brown fat-PPARA, PPARG, PPARGC1A, and UCP1-was high. Thus, loss of MEN1 and AIP is likely to be pathogenetically essential for hibernoma development. Simultaneous loss of two tumor suppressor genes has not previously been shown to result from a neoplasia-associated translocation. Furthermore, in contrast to the prevailing assumption that benign tumors harbor relatively few genetic aberrations, the present analyses demonstrate that a considerable number of chromosome breaks are involved in the pathogenesis of hibernoma. Global copy number analysis was performed using single nucleotide polymorphism (SNP) array. Cases 1-14 were hybridized onto Illumina Human1M-Duo v3.0 (and Human CNV370-Quad v3.0) BeadChip (Illumina, San Diego, CA, USA), following standard protocols supplied by the manufacturer. Case 15 was analyzed using Illumina Human Omni-Quad BeadChip. Normal blood DNA was analyzed in cases 1, 2, 4 and 6 using the Human CNV370-Quad v3.0 BeadChip. Data analysis was done using the BeadStudio software (Illumina).
2010-11-24 | E-GEOD-19040 | biostudies-arrayexpress