scholarly journals Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas

2017 ◽  
Vol 24 (8) ◽  
pp. 445-457 ◽  
Author(s):  
R Formosa ◽  
J Borg ◽  
J Vassallo
Keyword(s):  
Cell Cycle ◽  
Aryl Hydrocarbon Receptor ◽  
Pituitary Adenomas ◽  
Tumour Suppressor ◽  
Gh3 Cells ◽  
Altered Expression ◽  
Aryl Hydrocarbon ◽  
Cell Cycle Regulator ◽  
Regulator Genes

Pituitary adenomas (PA) represent the largest group of intracranial neoplasms and yet the molecular mechanisms driving this disease remain largely unknown. The aim of this study was to use a high-throughput screening method to identify molecular pathways that may be playing a significant and consistent role in PA. RNA profiling using microarrays on eight local PAs identified the aryl hydrocarbon receptor (AHR) signalling pathway as a key canonical pathway downregulated in all PA types. This was confirmed by real-time PCR in 31 tumours. The AHR has been shown to regulate cell cycle progression in various cell types; however, its role in pituitary tissue has never been investigated. In order to validate the role of AHR in PA behaviour, further functional studies were undertaken. Over-expression of AHR in GH3 cells revealed a tumour suppressor potential independent of exogenous ligand activation by benzo α-pyrene (BαP). Cell cycle analysis and quantitative PCR of cell cycle regulator genes revealed that both unstimulated and BαP-stimulated AHR reduced E2F-driven transcription and altered expression of cell cycle regulator genes, thus increasing the percentage of cells in G0/G1 phase and slowing the proliferation rate of GH3 cells. Co-immunoprecipitation confirmed the interaction between AHR and retinoblastoma (Rb1) protein supporting this as a functional mechanism for the observed reduction. Endogenous Ahr reduction using silencing RNA confirmed the tumour suppressive function of the Ahr. These data support a mechanistic pathway for the putative tumour suppressive role of AHR specifically in PA, possibly through its role as a cell cycle co-regulator, even in the absence of exogenous ligands.

scholarly journals AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells

2016 ◽  
Vol 23 (5) ◽  
pp. 433-443 ◽  
Author(s):  
Anne-Lise Lecoq ◽  
Say Viengchareun ◽  
Mirella Hage ◽  
Jérôme Bouligand ◽  
Jacques Young ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Protein Level ◽  
Pituitary Adenomas ◽  
Healthy Subjects ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
Gh3 Cells ◽  
Dependent Manner ◽  
Aryl Hydrocarbon ◽  
The Impact

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas through unknown molecular mechanisms. The best-known interacting partner of AIP is the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the effects of xenobiotics implicated in carcinogenesis. As 75% of AIP mutations disrupt the physical and/or functional interaction with AhR, we postulated that the tumorigenic potential of AIP mutations might result from altered AhR signaling. We evaluated the impact of AIP mutations on the AhR signaling pathway, first in fibroblasts from AIP-mutated patients with pituitary adenomas, by comparison with fibroblasts from healthy subjects, then in transfected pituitary GH3 cells. The AIP protein level in mutated fibroblasts was about half of that in cells from healthy subjects, but AhR expression was unaffected. Gene expression analyses showed significant modifications in the expression of the AhR target genes CYP1B1 and AHRR in AIP-mutated fibroblasts, both before and after stimulation with the endogenous AhR ligand kynurenine. Kynurenine increased Cyp1b1 expression to a greater extent in GH3 cells overexpressing wild type compared with cells expressing mutant AIP. Knockdown of endogenous Aip in these cells attenuated Cyp1b1 induction by the AhR ligand. Both mutant AIP expression and knockdown of endogenous Aip affected the kynurenine-dependent GH secretion of GH3 cells. This study of human fibroblasts bearing endogenous heterozygous AIP mutations and transfected pituitary GH3 cells shows that AIP mutations affect the AIP protein level and alter AhR transcriptional activity in a gene- and tissue-dependent manner.

Role of the aryl hydrocarbon receptor in cell cycle regulation

Toxicology ◽  
2002 ◽  
Vol 181-182 ◽  
pp. 171-177 ◽  
Author(s):  
Alvaro Puga ◽  
Jennifer Marlowe ◽  
Sonya Barnes ◽  
Ching-yi Chang ◽  
Andrew Maier ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Aryl Hydrocarbon Receptor ◽  
Cell Cycle Regulation ◽  
Aryl Hydrocarbon ◽  
Cycle Regulation

Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas

2007 ◽  
Vol 83 (2) ◽  
pp. 153-162 ◽  
Author(s):  
Atsuo Yoshino ◽  
Yoichi Katayama ◽  
Akiyoshi Ogino ◽  
Takao Watanabe ◽  
Kazunari Yachi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pituitary Adenomas ◽  
Promoter Hypermethylation ◽  
Cell Cycle Regulator ◽  
Regulator Genes

scholarly journals Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications

2009 ◽  
Vol 16 (3) ◽  
pp. 1029-1043 ◽  
Author(s):  
Marie-Lise Jaffrain-Rea ◽  
Mariolina Angelini ◽  
Donatella Gargano ◽  
Maria A Tichomirowa ◽  
Adrian F Daly ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Pituitary Adenomas ◽  
Pituitary Tumour ◽  
Clinical Implications ◽  
Rt Pcr ◽  
Interacting Protein ◽  
Non Invasive ◽  
Aryl Hydrocarbon ◽  
Sensitive Tool

Germline mutations of the aryl hydrocarbon receptor (AHR)-interacting protein (AIP) gene confer a predisposition to pituitary adenomas (PA), usually in the setting of familial isolated PA. To provide further insights into the possible role of AIP in pituitary tumour pathogenesis, the expression of AIP and AHR was determined by real-time RT-PCR and/or immunohistochemistry (IHC) in a large series of PA (n=103), including 17 with AIP mutations (AIPmut). Variable levels of AIP and AHR transcripts were detected in all PA, with a low AHR expression (P<0.0001 versus AIP). Cytoplasmic AIP and AHR were detected by IHC in 84.0 and 38.6% of PA respectively, and significantly correlated with each other (P=0.006). Nuclear AHR was detected in a minority of PA (19.7%). The highest AIP expression was observed in somatotrophinomas and non-secreting (NS) PA, and multivariate analysis in somatotrophinomas showed a significantly lower AIP immunostaining in invasive versus non-invasive cases (P=0.019). AIP expression was commonly low in other secreting PA. AIP immunostaining was abolished in a minority of AIPmut PA, with a frequent loss of cytoplasmic AHR and no evidence of nuclear AHR. In contrast, AIP overexpression in a subset of NS PA could be accompanied by nuclear AHR immunopositivity. We conclude that down-regulation of AIP and AHR may be involved in the aggressiveness of somatotrophinomas. Overall, IHC is a poorly sensitive tool for the screening of AIP mutations. Data obtained on AHR expression suggest that AHR signalling may be differentially affected according to PA phenotype.

scholarly journals p-Anilinoaniline Enhancement of Dioxin-Induced CYP1A1 Transcription and Aryl Hydrocarbon Receptor Occupancy of CYP1A1 Promoter: Role of the Cell Cycle

2012 ◽  
Vol 40 (5) ◽  
pp. 1032-1040 ◽  
Author(s):  
Althea Elliott ◽  
Aby Joiakim ◽  
Patricia A. Mathieu ◽  
Zofia Duniec-Dmuchowski ◽  
Thomas A. Kocarek ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Aryl Hydrocarbon Receptor ◽  
Receptor Occupancy ◽  
Aryl Hydrocarbon

scholarly journals The Role of the Aryl Hydrocarbon Receptor-Interacting Protein Gene in Familial and Sporadic Pituitary Adenomas

2008 ◽  
Vol 93 (6) ◽  
pp. 2390-2401 ◽  
Author(s):  
Chrysanthia A. Leontiou ◽  
Maria Gueorguiev ◽  
Jacqueline van der Spuy ◽  
Richard Quinton ◽  
Francesca Lolli ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Pituitary Adenomas ◽  
Protein Gene ◽  
Interacting Protein ◽  
Aryl Hydrocarbon
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