The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.
BACKGROUND
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.


METHODS
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.
Leontiou
Chrysanthia A
CA
Department of Endocrinology, Barts and the London School of Medicine, London, United Kingdom.
Gueorguiev
Maria
M
van der Spuy
Jacqueline
J
Quinton
Richard
R
Lolli
Francesca
F
Hassan
Sevda
S
Chahal
Harvinder S
HS
Igreja
Susana C
SC
Jordan
Suzanne
S
Rowe
Janice
J
Stolbrink
Marie
M
Christian
Helen C
HC
Wray
Jessica
J
Bishop-Bailey
David
D
Berney
Dan M
DM
Wass
John A H
JA
Popovic
Vera
V
Ribeiro-Oliveira
Antônio
A
Gadelha
Monica R
MR
Monson
John P
JP
Akker
Scott A
SA
Davis
Julian R E
JR
Clayton
Richard N
RN
Yoshimoto
Katsuhiko
K
Iwata
Takeo
T
Matsuno
Akira
A
Eguchi
Kuniki
K
Musat
Mâdâlina
M
Flanagan
Daniel
D
Peters
Gordon
G
Bolger
Graeme B
GB
Chapple
J Paul
JP
Frohman
Lawrence A
LA
Grossman
Ashley B
AB
Korbonits
Márta
M
D000172:Acromegaly / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002648:Child; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D019382:Human Growth Hormone; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4