Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas

Ritvonen, Elina; Pitkänen, Esa; Karppinen, Atte; Vehkavaara, Satu; Demi̇r, Hande; Paetau, Anders; Schalin‐Jäntti, Camilla; Karhu, Auli

doi:10.1530/eje-16-0620

Cited by 26 publications

(19 citation statements)

References 34 publications

(81 reference statements)

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“…Loss of this inhibitory G protein signal may be permissive for cellular proliferation and tumor growth. A strongly positive correlation between AIP and Gαi-2 protein expression has also been confirmed in sporadic somatotropinomas (73). The complex interplay between AIP and PKA signaling is further supported by the evidence that AIP interacts physically with both the regulatory (R1α) and the catalytic (Cα) subunits of PKA separately, as well as in complex (76).…”

Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 70%

“…Different types of pathogenic variants have been described leading to a truncated protein in many cases (11,71). Besides AHR, AIP has multiple other partners, including chaperones, phosphodiesterases, Gαi proteins, survivin, RET, nuclear receptors, such as thyroid hormone receptor β1, estrogen receptor-α, peroxisome proliferator-activated receptor-α, viral proteins and others (11,72,73). The cAMP-PKA signaling pathway is strongly implicated in pituitary tumorigenesis and the loss of AIP in mutated adenomas has been related to increased cAMP signaling through defective inhibitory Gα protein signaling.…”

Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 99%

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Somatic and germline mutations in the pathogenesis of pituitary adenomas

Vandeva

Daly

Pétrossians

et al. 2019

European Journal of Endocrinology

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Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

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Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 70%

Section: Aip Mutations In Fipa and Sporadic Pituitary Adenomasmentioning

confidence: 99%

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Vandeva

Daly

Pétrossians

et al. 2019

European Journal of Endocrinology

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“…The exact mechanisms linking AIP with the cAMP-dependent PKA pathway remain to be fully elucidated. In human AIP mutationpositive PAs, the expression of the G inhibitory protein Gα i-2 was found to be reduced compared to AIP mutationnegative tumours (Tuominen et al 2015), and the expression of AIP was found to be positively associated with that of Gα i-2 also in sporadic AIP mutation-negative PAs (Ritvonen et al 2017). Moreover, while knockdown of Gα i-2 and Gα i-3 led to a significant increase in cAMP in AIP WT cells, this effect was not observed in AIP-knockout cell lines (Tuominen et al 2015), suggesting that the loss of AIP can affect G inhibitory protein function.…”

Section: Aryl Hydrocarbon Receptor-interacting Proteinmentioning

confidence: 88%

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

Pepe

Korbonits

Iacovazzo

2019

Journal of Endocrinology

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While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15–30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune–Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune–Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.

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“…Recent studies performed on human and mouse somatotrophinomas demonstrated that AIP is essential to maintain relatively low levels of cAMP in normal somatotrophes, and the lack of AIP causes an accumulation of cAMP through defective Gαi-2 signalling, which leads to a downregulation of phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2) and p-CREB (Tuominen et al 2015). This point was supported by the fact that low Gαi-2 levels were observed in sporadic somatotrophinomas with decreased AIP immunoreactivity, and a positive association between AIP and Gαi-2 was found at protein level, which suggests a combined regulation (Ritvonen et al 2017). AIP expression was associated to higher Gαi-2 and lower Ki67.…”

Section: The Role Of Aip and Zac1 In Ssa Response In Somatotrophinomasmentioning

confidence: 93%

“…AIP was found to be associated with Gα13, Gαq and possibly regulate the abundance of Gαi-2 (Nakata et al 2009, Tuominen et al 2015, Ritvonen et al 2017. These interactions could influence multiple signalling pathways, with the Gαi-cAMP pathway being especially relevant regarding somatotroph cells and somatostatin action (see section below).…”

Section: Aryl Hydrocarbon Receptor (Ahr)mentioning

confidence: 99%

AIP and the somatostatin system in pituitary tumours

Ibáñez‐Costa

Korbonits

2017

Journal of Endocrinology

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Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

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Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas

Cited by 26 publications

References 34 publications

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Somatic and germline mutations in the pathogenesis of pituitary adenomas

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

AIP and the somatostatin system in pituitary tumours

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