The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.
Leontiou CA., Gueorguiev M., van der Spuy J., Quinton R., Lolli F., Hassan S., Chahal HS., Igreja SC., Jordan S., Rowe J., Stolbrink M., Christian HC., Wray J., Bishop-Bailey D., Berney DM., Wass JA., Popovic V., Ribeiro-Oliveira A., Gadelha MR., Monson JP., Akker SA., Davis JR., Clayton RN., Yoshimoto K., Iwata T., Matsuno A., Eguchi K., Musat M., Flanagan D., Peters G., Bolger GB., Chapple JP., Frohman LA., Grossman AB., Korbonits M.
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.