Details

Autor(en) / Beteiligte

• Tuominen, I
• Heliovaara, E
• Raitila, A
• Rautiainen, M-R
• Mehine, M
• Katainen, R
• Donner, I
• Aittomaeki, V
• Lehtonen, H J
• Ahlsten, M
• Kivipelto, L
• Schalin-Jaentti, C
• Arola, J
• Hautaniemi, S
• Karhu, A

Titel

AIP inactivation leads to pituitary tumorigenesis through defective G alpha sub(i)-cAMP signaling

Ist Teil von

• Oncogene, 2015-02, Vol.34 (9), p.1174-1184

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 alpha subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective G alpha sub(i-2) and G alpha sub(i-3) proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of G alpha sub(i-2) revealed that AIP deficiency is associated with a clear reduction in G alpha sub(i-2) protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective G alpha sub(i) signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent G alpha sub(i-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 G alpha sub(i) signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.