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Title: The role of the aryl hydrocarbon receptor interacting protein (AIP) in pituitary tumorigenesis : a proteomic approach for explaining the clinical behaviour of AIP mutation-associated pituitary adenomas
Author: Hernández Ramírez, Laura Cristina
ISNI:       0000 0004 7962 3162
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2015
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A subset of familial and sporadic pituitary adenomas is due to germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP). A systematic follow-up of cases and families with AIP mutation (AIPmut)-associated pituitary adenomas is lacking. The product of this novel tumour suppressor gene is a ubiquitously expressed co-chaperone of the heat shock proteins HSPA8 and HSP90, but besides of pituitary adenomas, there is no clear association of AIPmuts to other neoplasms. The molecular processes leading to pituitary tumorigenesis in the presence of AIPmuts and the mechanism for tissue-specific tumour suppressor function are unclear. This research work describes the clinical features of AIPmut positive familial and sporadic pituitary adenomas in a large international cohort of patients, aiming to increase the knowledge about this condition and focusing on the screening-led detection of pituitary adenomas. To define the repertoire of interactions of AIP in the pituitary gland and to determine which interactions are lost by AIP mutants, a proteomic screening for molecular partners of AIP in a pituitary cell line was conducted. The stability of a panel of missense AIP mutant proteins and the mechanism of protein degradation were evaluated in half-life studies, and the relationship between protein stability and phenotype was analysed. A number of novel features of AIPmut positive pituitary disease were identified, drawing attention to the high percentage of positive clinical screening of the apparently unaffected AIPmut carriers. The AIP tumour suppressor function is apparently mediated by its interaction with molecular chaperones, perhaps modifying their affinity for specific client proteins. AIP could exert an additional anti-tumorigenic action by regulating cytoskeletal organisation. AIP is processed via ubiquitination and proteasomal degradation, probably mediated by the FBXO3- containing SKP1-CUL1-F-BOX protein complex E3 ubiquitin-ligase. Enhanced proteasomal degradation conferred shorter half-life to most of the AIP mutants tested, with implications for the clinical presentation.
Supervisor: Not available Sponsor: National Council of Science and Technology (CONACYT) ; Secretariat of Public Education (SEP) Mexico ; Barts and The London Charity
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine ; Endocrinology ; Adenoma