ArticleOncogene2021
RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 17 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Genetics of familial acromegaly and pituitary gigantism.The Journal of clinical endocrinology and metabolism · 2026Review
- Aip mutation leads to significant alterations in gene expression, altered sensitivity to Ahr ligands, and early lethality in zebrafish.Frontiers in toxicology · 2026Article
- Synergistic prognostic value of transcription factor multiplicity and Ki-67 in pituitary neuroendocrine tumour recurrence after endoscopic transsphenoidal surgery: a novel tiered molecular risk model.Frontiers in endocrinology · 2026Article
- Functional analysis of AIP variants in a cohort of neuroendocrine neoplasms.Endocrine-related cancer · 2026Article
- Clinical and Genetic Spectrum of Large AIP Deletions.Human mutation · 2026Article
- Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis.European journal of endocrinology · 2025Article
- Detection of genetic mutations in 855 cases of papillary thyroid carcinoma by next generation sequencing and its clinicopathological features.Diagnostic pathology · 2024Article
- dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe.Nature communications · 2024Article
- Familial isolated pituitary adenoma is independent ofHeliyon · 2024Article
- Lysine Methyltransferase 5A Promotes the Progression of Growth Hormone Pituitary Neuroendocrine Tumors through the Wnt/β-Catenin Signaling Pathway.Neuroendocrinology · 2024Article
- Pituitary Tumorigenesis-Implications for Management.Medicina (Kaunas, Lithuania) · 2023Review
- 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
- Recent advances in understanding and managing pituitary adenomas.Faculty reviews · 2023Review
- Molecular targets in acromegaly.Frontiers in endocrinology · 2022Review
- Pituitary carcinoma: reclassification and implications in the NET schema.Endocrine oncology (Bristol, England) · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
15 authors at 3 institutions in 3 countries.
Funding
Abstract
It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.