title: The glucose-dependent insulinotropic polypeptide receptor is overexpressed amongst GNAS1 mutation-negative somatotropinomas and drives growth hormone (GH)-promoter activity in GH3 cells.
abstract: Somatic mutations in the GNAS1 gene, encoding the α-subunit of the heterotrimeric stimulatory G protein (Gαs), occur in approximately 40% of growth hormone (GH)-secreting pituitary tumours. By altering the adenylate cyclase-cAMP-protein kinase A pathway, they unequivocally give somatotroph cells a growth advantage. Hence, the pathogenesis of somatotropinomas could be linked to anomalies in receptors coupled to the cAMP second-messenger cascade. Among them, the glucose-dependent insulinotropic polypeptide receptor (GIPR) is already known to play a primary role in the impaired cAMP-dependent cortisol secretion in patients affected by food-dependent Cushing's syndrome. In the present study, 43 somatotropinomas and 12 normal pituitary glands were investigated for GIPR expression by quantitative reverse transcriptase-polymerase chain reaction, western blotting and immunohistochemistry. Tumoural specimens were also evaluated for GNAS1 mutational status. The effect of GIPR overexpression on cAMP levels and GH transcription was evaluated in an in vitro model of somatotropinomas, the GH-secreting pituitary cell line GH3. GIPR was expressed at higher levels compared to normal pituitaries in 13 GNAS1 mutation-negative somatotropinomas. GIP stimulated adenylyl cyclase and GH-promoter activity in GIPR-transfected GH3 cells, confirming a correct coupling of GIPR to Gαs. In a proportion of acromegalic patients, GIPR overexpression appeared to be associated with a paradoxical increase in GH after an oral glucose tolerance test. Whether GIPR overexpression in acromegalic patients may be associated with this paradoxical response or more generally involved in the pathogenesis of acromegaly, as suggested by the mutually exclusive high GIPR levels and GNAS1 mutations, remains an open question.
authors.affiliation: Endocrinology Division, Department of Medical and Surgical Sciences, Hospital/University of Padova, Padova, Italy. gianluca.occhi@unipd.it
authors.forename: G
authors.initials: G
authors.lastname: Occhi
authors.forename: M
authors.initials: M
authors.lastname: Losa
authors.forename: N
authors.initials: N
authors.lastname: Albiger
authors.forename: G
authors.initials: G
authors.lastname: Trivellin
authors.forename: D
authors.initials: D
authors.lastname: Regazzo
authors.forename: M
authors.initials: M
authors.lastname: Scanarini
authors.forename: J L
authors.initials: JL
authors.lastname: Monteserin-Garcia
authors.forename: B
authors.initials: B
authors.lastname: Fröhlich
authors.forename: S
authors.initials: S
authors.lastname: Ferasin
authors.forename: M R
authors.initials: MR
authors.lastname: Terreni
authors.forename: A
authors.initials: A
authors.lastname: Fassina
authors.forename: L
authors.initials: L
authors.lastname: Vitiello
authors.forename: G
authors.initials: G
authors.lastname: Stalla
authors.forename: F
authors.initials: F
authors.lastname: Mantero
authors.forename: C
authors.initials: C
authors.lastname: Scaroni
mesh_terms: D000172:Acromegaly / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019382:Human Growth Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism; D052683:Somatotrophs / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D002864:Chromogranins; D011964:Receptors, Gastrointestinal Hormone; D019382:Human Growth Hormone; C041086:gastric inhibitory polypeptide receptor; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs