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
Abstract
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.
Authors
Hernández Ramírez, Laura CristinaCollections
- Theses [3705]