AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling
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 pituita...
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Published in | Oncogene Vol. 34; no. 9; pp. 1174 - 1184 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
26.02.2015
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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 Gα
i-2
and Gα
i-3
proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Gα
i-2
revealed that AIP deficiency is associated with a clear reduction in Gα
i-2
protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gα
i
signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Gα
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 Gα
i
signaling underlies the development of GH-secreting pituitary adenomas in
AIP
mutation carriers. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2014.50 |