Aryl Hydrocarbon Receptor Interacting Protein Maintains Germinal Center B Cells through Suppression of BCL6 Degradation

Sun, Dijue; Stopka‐Farooqui, Urszula; Barry, Sayka; Aksoy, Ezra; Parsonage, Gregory; Vossenkämper, Anna; Capasso, Melania; Wan, Xinyu; Norris, Sherine; Marshall, Jennifer L.; Clear, Andrew; Gribben, John G.; MacDonald, Thomas T.; Buckley, Christopher D.; Korbonits, Márta; Haworth, Oliver

doi:10.1016/j.celrep.2019.04.014

Cited by 24 publications

(23 citation statements)

References 57 publications

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“…Increased GH release has been found in AIP-disrupted cells, probably associated with the increased STAT3 phosphorylation ( 41 , 46 ), while an altered microenvironment may also explain the aggressive phenotype of some of these tumors ( 47 ). However, the role of other AIP partners—nuclear receptors (AHR, ER, GR, PPRα, TRβ1), mitochondrial proteins, survivin (reviewed in ( 48 )) or BCL6 ( 49 ) in the pituitary-specific effects is unclear.…”

Section: Genetic Mechanisms Of Tumorigenesismentioning

confidence: 99%

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Nadhamuni

Korbonits

2020

Endocrine Reviews

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Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or non-syndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and non-coding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multi-omics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis.

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Section: Genetic Mechanisms Of Tumorigenesismentioning

confidence: 99%

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Nadhamuni

Korbonits

2020

Endocrine Reviews

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“…Being a chaperone, not surprisingly several novel interacting proteins have been described for AIP [ 17 ] and miR34 has also emerged in two independent studies as a related key microRNA [ 18 , 19 ]. Knowledge derived from cell-based experiments considers AIP as a tumour suppressor in some cell types [ 7 , 8 , 15 ], but not all [ 20 ]. Global knockout in mice, Drosophila and C. elegans shows embryonic lethality [ 21 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas

et al. 2021

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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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“…Data from studies screening all human organs confirmed AIP mRNA expression in 36 studied tissues ( 37 ). We have recently identified a role of AIP in lymphocytes, which could be a source of circulating AIP ( 38 ). A close correlation between AIP and GH levels may not be expected due to their highly discrepant half-lives, being in the order of 30 h for AIP compared to only 16 min for GH ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion

Stojanović

Stiles

et al. 2019

Endocrine Connections

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Background Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients. Subjects and methods Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP. Results Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT. Conclusions Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

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Aryl Hydrocarbon Receptor Interacting Protein Maintains Germinal Center B Cells through Suppression of BCL6 Degradation

Cited by 24 publications

References 57 publications

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion

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