title: The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.
abstract: 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.
authors.affiliation: Department of Endocrinology, Barts and the London School of Medicine, London, United Kingdom.
authors.forename: Chrysanthia A
authors.initials: CA
authors.lastname: Leontiou
authors.forename: Maria
authors.initials: M
authors.lastname: Gueorguiev
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van der Spuy
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.forename: Francesca
authors.initials: F
authors.lastname: Lolli
authors.forename: Sevda
authors.initials: S
authors.lastname: Hassan
authors.forename: Harvinder S
authors.initials: HS
authors.lastname: Chahal
authors.forename: Susana C
authors.initials: SC
authors.lastname: Igreja
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jordan
authors.forename: Janice
authors.initials: J
authors.lastname: Rowe
authors.forename: Marie
authors.initials: M
authors.lastname: Stolbrink
authors.forename: Helen C
authors.initials: HC
authors.lastname: Christian
authors.forename: Jessica
authors.initials: J
authors.lastname: Wray
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
authors.forename: Dan M
authors.initials: DM
authors.lastname: Berney
authors.forename: John A H
authors.initials: JA
authors.lastname: Wass
authors.forename: Vera
authors.initials: V
authors.lastname: Popovic
authors.forename: Antônio
authors.initials: A
authors.lastname: Ribeiro-Oliveira
authors.forename: Monica R
authors.initials: MR
authors.lastname: Gadelha
authors.forename: John P
authors.initials: JP
authors.lastname: Monson
authors.forename: Scott A
authors.initials: SA
authors.lastname: Akker
authors.forename: Julian R E
authors.initials: JR
authors.lastname: Davis
authors.forename: Richard N
authors.initials: RN
authors.lastname: Clayton
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwata
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuno
authors.forename: Kuniki
authors.initials: K
authors.lastname: Eguchi
authors.forename: Mâdâlina
authors.initials: M
authors.lastname: Musat
authors.forename: Daniel
authors.initials: D
authors.lastname: Flanagan
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.forename: Graeme B
authors.initials: GB
authors.lastname: Bolger
authors.forename: J Paul
authors.initials: JP
authors.lastname: Chapple
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Frohman
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: 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
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D019382:Human Growth Hormone; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4