ArticleOncogene2015
AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 109 citations in OpenAlex.
- Higher ARNT expression is associated with the sparsely granulated phenotype in somatotroph pituitary adenomas: An immunohistochemical study.Pituitary · 2026Article
- Genetics of familial acromegaly and pituitary gigantism.The Journal of clinical endocrinology and metabolism · 2026Review
- AIP expression and imaging findings in somatotroph adenomas after pre-operative lanreotide therapy for acromegaly.Pituitary · 2026Article
- Using fish models to understand the role of aryl hydrocarbon receptor (AHR)-interacting protein (AIP) in controlling sensitivity and resistance to dioxin-like compounds in vivo.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Clinical and Genetic Spectrum of Large AIP Deletions.Human mutation · 2026Article
- Functional analysis of AIP variants in a cohort of neuroendocrine neoplasms.Endocrine-related cancer · 2026Article
- Single-cell and spatial transcriptome analyses reveal tumor heterogeneity and immune remodeling involved in pituitary neuroendocrine tumor progression.Nature communications · 2025Article
- A Brief Overview of Molecular Biology in Pituitary Adenomas with a Focus on Aggressive Lesions.International journal of molecular sciences · 2025Review
- Identification of a coagulation-related gene signature for predicting prognosis in recurrent glioma.Discover oncology · 2024Article
- Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.Endocrine · 2024Article
- Molecular targets in acromegaly.Frontiers in endocrinology · 2022Review
- RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas.Oncogene · 2021Article
- Drug resistance in pituitary tumours: from cell membrane to intracellular signalling.Nature reviews. Endocrinology · 2021Review
- Somatotroph Tumors and the Epigenetic Status of theInternational journal of molecular sciences · 2021Article
- Metabolic Reprogramming Drives Pituitary Tumor Growth through Epigenetic Regulation of TERT.Acta histochemica et cytochemica · 2021Article
- Genetics of Acromegaly and Gigantism.Journal of clinical medicine · 2021Review
- Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms.Endocrine reviews · 2020Review
- G Protein-Coupled receptors and heterotrimeric G proteins as cancer drivers.FEBS letters · 2020Review
- Oncogene-induced DNA damage: cyclic AMP steps into the ring.The Journal of clinical investigation · 2020Article
- Prkar1a haploinsufficiency ameliorates the growth hormone excess phenotype in Aip-deficient mice.Human molecular genetics · 2020Article
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
The aryl hydrocarbon receptor interacting protein (AIP) is a tumor-suppressor gene underlying the pituitary adenoma predisposition. Thus far, the exact molecular mechanisms by which inactivated AIP exerts its tumor-promoting action have been unclear. To better understand the role of AIP in pituitary tumorigenesis, we performed gene expression microarray analysis to examine changes between Aip wild-type and knockout mouse embryonic fibroblast (MEF) cell lines. Transcriptional analyses implied that Aip deficiency causes a dysfunction in cyclic adenosine monophosphate (cAMP) signaling, as well as impairments in signaling cascades associated with developmental and immune-inflammatory responses. In vitro experiments showed that AIP deficiency increases intracellular cAMP concentrations in both MEF and murine pituitary adenoma cell lines. Based on knockdown of various G protein α subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective Gαi-2 and Gαi-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Gαi-2 revealed that AIP deficiency is associated with a clear reduction in Gαi-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gαi signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Gαi-2 protein levels, irrespective of Aip mutation status. We additionally observed reduced expression of phosphorylated extracellular signal-regulated kinases 1/2 and cAMP response element-binding protein levels in mouse and human AIP-deficient somatotropinomas. This study implies for the first time that a failure to inhibit cAMP synthesis through dysfunctional Gαi signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.
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