title: AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling.
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.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: I
authors.initials: I
authors.lastname: Tuominen
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Heliövaara
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Raitila
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: M-R
authors.initials: MR
authors.lastname: Rautiainen
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Mehine
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Katainen
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: I
authors.initials: I
authors.lastname: Donner
authors.affiliation: Systems Biology Laboratory, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: V
authors.initials: V
authors.lastname: Aittomäki
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lehtonen
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Ahlsten
authors.affiliation: Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Kivipelto
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: C
authors.initials: C
authors.lastname: Schalin-Jäntti
authors.affiliation: Department of Pathology, HUSLAB, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Arola
authors.affiliation: Systems Biology Laboratory, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Hautaniemi
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Karhu
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology*; D010911:Pituitary Neoplasms / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go