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The Role of the Aryl Hydrocarbon Receptor-Interacting Protein Gene in Familial and Sporadic Pituitary Adenomas

Departments of Endocrinology (C.A.L., M.G., F.L., S.H., H.S.C., S.C.J., J.P.M., S.A.A., J.P.C., A.B.G., M.K.) and Histopathology (S.J., D.M.B.) and William Harvey Research Institute (J.W., D.B.-B.), Barts and the London School of Medicine, United Kingdom EC1M 6BQ; Institute of Ophthalmology (J.v.d.S.), University College London, United Kingdom EC1V 9EL; Department of Endocrinology (R.Q.), Royal Victoria Infirmary and University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom NE1 4LP; London Research Institute Cancer Research, UK (J.R., G.P.), London, United Kingdom WC2A 3PX; Department of Anatomy (M.S., H.C.C.), University of Oxford, Oxford, United Kingdom OX1 3QX; Department of Endocrinology (J.A.H.W.), Churchill Hospital, Oxford, United Kingdom OX3 7LJ; Department of Endocrinology (V.P.), University Clinical Center, Belgrade, Serbia 11000; Department of Internal Medicine (A.R.-O.), Federal University of Minas Gerais, 30330-120 Belo Horizonte, Brazil; Hospital Universitário Clementino Fraga Filho (M.R.G.), Universidade Federal do Rio de Janeiro, 21949-590 Rio de Janeiro, Brazil; Department of Endocrinology (J.R.E.D.), University of Manchester, Manchester, United Kingdom M13 9PT; Department of Endocrinology (R.N.C.), University Hospital of North Staffordshire, Stoke-on-Trent, United Kingdom ST4 6QG; Department of Medical Pharmacology (K.Y., T.I.), The University of Tokushima, Tokushima 770-8504 Japan; Department of Neurosurgery (A.M.), Teikyo University, Ichihara City, Chiba 299-0111, Japan; Department of Neurosurgery (K.E.), Hiroshima University, Hiroshima 734-8551, Japan; Department of Endocrinology (M.M.), Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 020021; Endocrinology (D.F.), Derriford Hospital, Portsmouth, United Kingdom PL6 8DH; Comprehensive Cancer Center (G.B.B.), University of Alabama, Birmingham, Alabama 35294; and Department of Endocrinology (L.A.F.), University of Illinois at Chicago, Chicago, Illinois 60608

Address all correspondence and requests for reprints to: Márta Korbonits, Department of Endocrinology, Barts and the London School of Medicine, London, United Kingdom EC1A 6BQ. 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: Twenty-six FIPA kindreds and 85 sporadic pituitary adenoma patients were included in the study.

Results: Nine families harbored AIP mutations. Overexpression of wild-type AIP in TIG3 and HEK293 human fibroblast and GH3 pituitary cell lines dramatically reduced cell proliferation, whereas 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 colocalizes exclusively with GH 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, whereas AIP is expressed in the secretory vesicle in GH-secreting tumors, similar to normal GH-secreting cells, in lactotroph, corticotroph, and nonfunctioning 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.

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