The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2008
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| _version_ | 1797065075337461760 |
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| author | Leontiou, C Gueorguiev, M van der Spuy, J Quinton, R Lolli, F Hassan, S Chahal, H Igreja, S Jordan, S Rowe, J Stolbrink, M Christian, H Wray, J Bishop-Bailey, D Berney, D Wass, J Popovic, V Ribeiro-Oliveira, A Gadelha, MR Monson, J Akker, SA Davis, JR Clayton, R Yoshimoto, K Iwata, T |
| author_facet | Leontiou, C Gueorguiev, M van der Spuy, J Quinton, R Lolli, F Hassan, S Chahal, H Igreja, S Jordan, S Rowe, J Stolbrink, M Christian, H Wray, J Bishop-Bailey, D Berney, D Wass, J Popovic, V Ribeiro-Oliveira, A Gadelha, MR Monson, J Akker, SA Davis, JR Clayton, R Yoshimoto, K Iwata, T |
| author_sort | Leontiou, C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:23:27Z |
| format | Journal article |
| id | oxford-uuid:4244d29c-1f97-48da-9ad2-ce4e7d657de5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:23:27Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:4244d29c-1f97-48da-9ad2-ce4e7d657de52022-03-26T14:48:35ZThe role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4244d29c-1f97-48da-9ad2-ce4e7d657de5EnglishSymplectic Elements at Oxford2008Leontiou, CGueorguiev, Mvan der Spuy, JQuinton, RLolli, FHassan, SChahal, HIgreja, SJordan, SRowe, JStolbrink, MChristian, HWray, JBishop-Bailey, DBerney, DWass, JPopovic, VRibeiro-Oliveira, AGadelha, MRMonson, JAkker, SADavis, JRClayton, RYoshimoto, KIwata, T 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. |
| spellingShingle | Leontiou, C Gueorguiev, M van der Spuy, J Quinton, R Lolli, F Hassan, S Chahal, H Igreja, S Jordan, S Rowe, J Stolbrink, M Christian, H Wray, J Bishop-Bailey, D Berney, D Wass, J Popovic, V Ribeiro-Oliveira, A Gadelha, MR Monson, J Akker, SA Davis, JR Clayton, R Yoshimoto, K Iwata, T The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. |
| title | The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. |
| title_full | The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. |
| title_fullStr | The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. |
| title_full_unstemmed | The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. |
| title_short | The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. |
| title_sort | role of the aryl hydrocarbon receptor interacting protein gene in familial and sporadic pituitary adenomas |
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