AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling
| Autor: | Elina Heliövaara, Sampsa Hautaniemi, Leena Kivipelto, I. Tuominen, M-R Rautiainen, Riku Katainen, V. Aittomaki, Anniina Raitila, Miika Mehine, Auli Karhu, Camilla Schalin-Jäntti, Manuel Ahlsten, Heli J. Lehtonen, Iikki Donner, Johanna Arola |
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| Rok vydání: | 2014 |
| Předmět: |
Adenoma
Cancer Research G protein Gi alpha subunit 030209 endocrinology & metabolism GTP-Binding Protein alpha Subunits Gi-Go Biology Cell Line Adenylyl cyclase Gene Knockout Techniques Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cyclic AMP Genetics Animals Humans Pituitary Neoplasms Cyclic adenosine monophosphate Molecular Biology 030304 developmental biology 0303 health sciences Kinase Intracellular Signaling Peptides and Proteins Fibroblasts Aryl hydrocarbon receptor Molecular biology Cell biology Cell Transformation Neoplastic chemistry Pituitary Gland Knockout mouse biology.protein Signal transduction Signal Transduction |
| Zdroj: | Oncogene. 34:1174-1184 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2014.50 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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