AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling.
Oncogene, 2015/2/26;34(9):1174-84.
Tuominen I[1], Heliövaara E[1], Raitila A[1], Rautiainen MR[1], Mehine M[1], Katainen R[1], Donner I[1], Aittomäki V[2], Lehtonen HJ[1], Ahlsten M[1], Kivipelto L[3], Schalin-Jäntti C[4], Arola J[5], Hautaniemi S[2], Karhu A[1]
Affiliations
PMID: 24662816DOI: 10.1038/onc.2014.50
Impact factor: 8.756
Abstract
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 α subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective Gαi-2 and Gαi-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Gαi-2 revealed that AIP deficiency is associated with a clear reduction in Gαi-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gαi signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Gαi-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 Gαi signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.
MeSH terms
Adenoma; Animals; Cell Line; Cell Transformation, Neoplastic; Cyclic AMP; Fibroblasts; GTP-Binding Protein alpha Subunits, Gi-Go; Gene Knockout Techniques; Humans; Intracellular Signaling Peptides and Proteins; Mice; Pituitary Gland; Pituitary Neoplasms; Signal Transduction
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