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This version published online on April 15, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-2611
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Submitted on November 27, 2007
Accepted on March 26, 2008

THE ROLE OF THE AIP GENE IN FAMILIAL AND SPORADIC PITUITARY ADENOMAS

Chrysanthia A Leontiou, Maria Gueorguiev, Jacqueline van der Spuy, Richard Quinton, Francesca Lolli, Sevda Hassan, Harvinder S Chahal, Susana C Igreja, Suzanne Jordan, Janice Rowe, Marie Stolbrink, Helen C Christian, Jessica Wray, David Bishop-Bailey, Dan M Berney, John AH Wass, Vera Popovic, Antônio Ribeiro-Oliveira Jr, Monica R Gadelha, John P Monson, Scott A Akker, Julian RE Davis, Richard N Clayton, Katsuhiko Yoshimoto, Takeo Iwata, Akira Matsuno, Kuniki Eguchi, Mâdâlina Musat, Gordon Peters, Graeme B Bolger, J Paul Chapple, Lawrence A Frohman, Ashley B Grossman, and Márta Korbonits*

Endocrinology, Histopathology and WHRI, Barts and the London Medical School, UK, EC1M 6BQ; Institute of Ophthalmology, University College London, UK, EC1V 9EL; Endocrinology, Royal Victoria Infirmary and University of Newcastle-upon-Tyne, UK, NE1 4LP; London Research Institute CRUK, London, United Kingdom, WC2A 3PX; Anatomy, University of Oxford, Oxford, United Kingdom, OX1 3QX; Endocrinology, Churchill Hospital Oxford, UK, OX3 7LJ; Endocrinology University Clinical Center, Belgrade, Serbia, 11000; Internal Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil, 30330-120; Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Brazil, 21949-590; Endocrinology, University of Manchester, Manchester, United Kingdom, M13 9PT; Endocrinology, University Hospital of North Staffordshire, Stoke-On-Trent, UK, ST4 6QG; Department of Medical Pharmacology, The University of Tokushima, 770-8504, Japan; Neurosurgery, Teikyo University, Ichihara City, Chiba, 299-0111, Japan; Neurosurgery, Hiroshima University, 734-8551, Japan; Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania, 020021; Comprehensive Cancer Center, University of Alabama, Birmingham AL, USA, 35294; Endocrinology, University of Illinois at Chicago, Chicago, USA, 60608

* To whom correspondence should be addressed. E-mail: m.korbonits{at}qmul.ac.uk.

Context: Mutations have been identified in the aryl hydrocarbon receptor-interacting protein (AIP) gene in familial isolated pituitary adenomas (FIPA). It is not clear, however, how this molecular chaperone is involved in tumorigenesis.

Objective: AIP sequence changes and expression were studied in FIPA and sporadic adenomas. The function of normal and mutated AIP molecules was studied on cell proliferation and protein-protein interaction. Cellular and ultrastructural AIP localization was determined in pituitary cells.

Patients: 26 FIPA kindreds and 85 sporadic pituitary adenoma patients.

Results: Nine families harbored AIP mutations. Over-expression of wild-type AIP in TIG3 and HEK293 human fibroblast and GH3 pituitary cell lines dramatically reduced cell proliferation, while mutant AIP lost this ability. All the mutations led to a disruption of the protein-protein interaction between AIP and phosphodiesterase-4A5. In normal pituitary, AIP co-localizes exclusively with growth hormone and prolactin, and it is found in association with the secretory vesicle, as shown by double-immunofluorescence and electron microscopy staining. In sporadic pituitary adenomas, however, AIP is expressed in all tumor types. In addition, while AIP is expressed in the secretory vesicle in growth hormone-secreting tumors, similar to normal growth hormone-secreting cells, in lactotroph, corticotroph and non-functioning adenomas it is localized to the cytoplasm and not in the secretory vesicles.

Conclusions: Our functional evaluation of AIP mutations is consistent with a tumor-suppressor role for AIP and its involvement in familial acromegaly. The abnormal expression and subcellular localization of AIP in sporadic pituitary adenomas indicate deranged regulation of this protein during tumorigenesis.
Key words: pituitary adenoma • familial disease • AIP • cell proliferation • tumor suppressor gene




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