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AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE37927 | GEO | 2014/03/05

SECONDARY ACCESSION(S): PRJNA165687

REPOSITORIES: GEO

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AIP inactivation exerts its tumor-promoting action through defected GÎ±i signaling and elevated cyclic-AMP levels

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

Identification of distinct molecular signatures in AIP mutation-positive familial isolated pituitary adenomas

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

miR-34a is upregulated in AIP mutated pituitary adenomas and induces octreotide-resistant cell proliferation and growth hormone secretion

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

cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors.

Project description: Not available

| S-EPMC4901527 | biostudies-literature

Loss of the tumor suppressor gene AIP mediates the browning of human brown fat tumors

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

Trophoblast epithelial-mesenchymal transition (EMT) in abnormally invasive placenta (AIP)

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

Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma

2010-11-24 | GSE19040 | GEO

AIP and MEN1 mutations and AIP immunohistochemistry in pituitary adenomas in a tertiary referral center.

Project description: Not available

| S-EPMC6432872 | biostudies-literature

Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression.

Project description: Not available

| S-EPMC2947291 | biostudies-literature

Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma

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

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