Research Papers:

Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland

Laura C. Hernández-Ramírez, Rhodri M.L. Morgan, Sayka Barry, Fulvio D’Acquisto, Chrisostomos Prodromou and Márta Korbonits _

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Oncotarget. 2018; 9:9177-9198. https://doi.org/10.18632/oncotarget.24183

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Laura C. Hernández-Ramírez1,4, Rhodri M.L. Morgan2,5, Sayka Barry1, Fulvio D’Acquisto3, Chrisostomos Prodromou2 and Márta Korbonits1

1Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK

2Genome Damage and Stability Centre, University of Sussex, Brighton, Falmer, BN1 9RQ, UK

3Centre for Microvascular Research, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK

4Present address: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892-1862, USA

5Present address: Protein Crystallography Facility, Centre for Structural Biology, Flowers Building, Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK

Correspondence to:

Márta Korbonits, email: m.korbonits@qmul.ac.uk

Keywords: AIP; co-chaperone; quantitative mass spectrometry; acromegaly; FIPA

Received: May 18, 2017     Accepted: January 01, 2018     Published: January 11, 2018


Despite the well-recognized role of loss-of-function mutations of the aryl hydrocarbon receptor interacting protein gene (AIP) predisposing to pituitary adenomas, the pituitary-specific function of this tumor suppressor remains an enigma. To determine the repertoire of interacting partners for the AIP protein in somatotroph cells, wild-type and variant AIP proteins were used for pull-down/quantitative mass spectrometry experiments against lysates of rat somatotropinoma-derived cells; relevant findings were validated by co-immunoprecipitation and co-localization. Global gene expression was studied in AIP mutation positive and negative pituitary adenomas via RNA microarrays. Direct interaction with AIP was confirmed for three known and six novel partner proteins. Novel interactions with HSPA5 and HSPA9, together with known interactions with HSP90AA1, HSP90AB1 and HSPA8, indicate that the function/stability of multiple chaperone client proteins could be perturbed by a deficient AIP co-chaperone function. Interactions with TUBB, TUBB2A, NME1 and SOD1 were also identified. The AIP variants p.R304* and p.R304Q showed impaired interactions with HSPA8, HSP90AB1, NME1 and SOD1; p.R304* also displayed reduced binding to TUBB and TUBB2A, and AIP-mutated tumors showed reduced TUBB2A expression. Our findings suggest that cytoskeletal organization, cell motility/adhesion, as well as oxidative stress responses, are functions that are likely to be involved in the tumor suppressor activity of AIP.

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