Journal
ONCOGENE
Volume 34, Issue 9, Pages 1174-1184Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2014.50
Keywords
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Funding
- Academy of Finland [250345]
- Cancer Society of Finland [4700325]
- Novo Nordisk Foundation [A14582]
- Association for International Cancer Research [13-1075]
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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 a subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective G alpha(i)-2 and G alpha(i)-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of G alpha(i)-2 revealed that AIP deficiency is associated with a clear reduction in G alpha(i)-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gai signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent G alpha(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(i) signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.
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