ArticleThe Journal of clinical endocrinology and metabolism2016
Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations.
Article in The Journal of clinical endocrinology and metabolism, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 59 citations in OpenAlex.
- Genetics of familial acromegaly and pituitary gigantism.The Journal of clinical endocrinology and metabolism · 2026Review
- 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
- Identification and functional analysis of a novel TBC1D23 pathogenic variant in a Chinese family with pontocerebellar hypoplasia.Human genomics · 2025Article
- Disentangling the mutational effects on protein stability and interaction of human MLH1.PLoS genetics · 2025Article
- Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis.European journal of endocrinology · 2025Article
- SKP1-CUL1-F-box: Key molecular targets affecting disease progression.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Review
- Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants.Nature communications · 2024Article
- The Spectrum of Familial Pituitary Neuroendocrine Tumors.Endocrine pathology · 2023Review
- The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in theFrontiers in endocrinology · 2023Article
- Article
- N-glycosylation of somatostatin receptor type 2 protects rats from acute pancreatitis.Annals of translational medicine · 2021Article
- 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
- Diverse Roles of F-BoxProtein3 in Regulation of Various Cellular Functions.Frontiers in cell and developmental biology · 2021Review
- Cancer-derived UTX TPR mutations G137V and D336G impair interaction with MLL3/4 complexes and affect UTX subcellular localization.Oncogene · 2020Article
- Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12.The Journal of biological chemistry · 2020Article
- The Pituitary Tumors and Their Tumor-Specific Microenvironment.Advances in experimental medicine and biology · 2020Article
- Aryl Hydrocarbon Receptor Interacting Protein Maintains Germinal Center B Cells through Suppression of BCL6 Degradation.Cell reports · 2019Article
- Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.Endocrine connections · 2019Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
contextThe pathogenic effect of mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts.
objectiveThis study sought to analyze the mechanism/speed of protein turnover of wild-type and missense AIP variants, correlating protein half-life with clinical parameters. DESIGN AND
settingHalf-life and protein-protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed in a clinical academic research institution. PATIENTS: Data were obtained from our cohort of pituitary adenoma patients and literature-reported cases.
interventionsProtein turnover of endogenous AIP in two cell lines and fifteen AIP variants overexpressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. Glutathione-S-transferase pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by coimmunoprecipitation and gene knockdown. Relevant clinical data was collected.
main outcome measuresHalf-life of wild-type and mutant AIP proteins and its correlation with clinical parameters.
resultsEndogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7 h). AIP variants were divided into stable proteins (median, 77.7 h; interquartile range [IQR], 60.7-92.9 h), and those with short (median, 27 h; IQR, 21.6-28.7 h) or very short (median, 7.7 h; IQR, 5.6-10.5 h) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r = 0.411; P = .002). The FBXO3-containing SKP1-CUL1-F-box protein complex was identified as the E3 ubiquitin-ligase recognizing AIP.
conclusionsAIP is a stable protein, driven to ubiquitination by the SKP1-CUL1-F-box protein complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype.
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