TY - JOUR
T1 - The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas
AU - Leontiou, Chrysanthia A.
AU - Gueorguiev, Maria
AU - Van Der Spuy, Jacqueline
AU - Quinton, Richard
AU - Lolli, Francesca
AU - Hassan, Sevda
AU - Chahal, Harvinder S.
AU - Igreja, Susana C.
AU - Jordan, Suzanne
AU - Rowe, Janice
AU - Stolbrink, Marie
AU - Christian, Helen C.
AU - Wray, Jessica
AU - Bishop-Bailey, David
AU - Berney, Dan M.
AU - Wass, John A.H.
AU - Popovic, Vera
AU - Ribeiro-Oliveira, Antônio
AU - Gadelha, Monica R.
AU - Monson, John P.
AU - Akker, Scott A.
AU - Davis, Julian R.E.
AU - Clayton, Richard N.
AU - Yoshimoto, Katsuhiko
AU - Iwata, Takeo
AU - Matsuno, Akira
AU - Eguchi, Kuniki
AU - Musat, Mâdâlina
AU - Flanagan, Daniel
AU - Peters, Gordon
AU - Bolger, Graeme B.
AU - Chapple, J. Paul
AU - Frohman, Lawrence A.
AU - Grossman, Ashley B.
AU - Korbonits, Márta
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=45149085453&partnerID=8YFLogxK
U2 - 10.1210/jc.2007-2611
DO - 10.1210/jc.2007-2611
M3 - Article
C2 - 18381572
AN - SCOPUS:45149085453
SN - 0021-972X
VL - 93
SP - 2390
EP - 2401
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 6
ER -