| First Author | Tuominen I | Year | 2015 |
| Journal | Oncogene | Volume | 34 |
| Issue | 9 | Pages | 1174-84 |
| PubMed ID | 24662816 | Mgi Jnum | J:315307 |
| Mgi Id | MGI:6830054 | Doi | 10.1038/onc.2014.50 |
| Citation | Tuominen I, et al. (2015) AIP inactivation leads to pituitary tumorigenesis through defective Galphai-cAMP signaling. Oncogene 34(9):1174-84 |
| abstractText | 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 Galphai-2 and Galphai-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Galphai-2 revealed that AIP deficiency is associated with a clear reduction in Galphai-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Galphai signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Galphai-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 Galphai signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers. |
