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AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling

Oncogene volume 34, pages 1174–1184 (2015)Cite this article

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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.

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Acknowledgements

We thank Inga-Lill Svedberg, Mairi Kuris, Alison Ollikainen and Iina Vuoristo for technical assistance. The Biomedicum Imaging Unit is acknowledged for the microscopy service and the Biomedicum Functional Genomics Unit (FuGU) for expression array and virus core services. This study was supported by the Academy of Finland (250345), the Cancer Society of Finland (4700325), the Novo Nordisk Foundation (A14582) and the Association for International Cancer Research (13–1075). This work was supported in part by the Novo Nordisk Foundation (AK).

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Author notes

  1. I Tuominen

    Present address: 7Current address: Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.,

  2. M-R Rautiainen

    Present address: 8Current address: Public Health Genomics Unit and Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland.,

  3. I Tuominen and E Heliövaara: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    I Tuominen, E Heliövaara, A Raitila, M-R Rautiainen, M Mehine, R Katainen, I Donner, H J Lehtonen, M Ahlsten & A Karhu

  2. Systems Biology Laboratory, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    V Aittomäki & S Hautaniemi

  3. Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    L Kivipelto

  4. Division of Endocrinology, Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    C Schalin-Jäntti

  5. Department of Pathology, HUSLAB, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, Helsinki, Finland

    J Arola

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Tuominen, I., Heliövaara, E., Raitila, A. et al. AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling. Oncogene 34, 1174–1184 (2015). https://doi.org/10.1038/onc.2014.50

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