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

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          Abstract

          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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          Most cited references108

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          Systematic and quantitative assessment of the ubiquitin-modified proteome.

          Despite the diverse biological pathways known to be regulated by ubiquitylation, global identification of substrates that are targeted for ubiquitylation has remained a challenge. To globally characterize the human ubiquitin-modified proteome (ubiquitinome), we utilized a monoclonal antibody that recognizes diglycine (diGly)-containing isopeptides following trypsin digestion. We identify ~19,000 diGly-modified lysine residues within ~5000 proteins. Using quantitative proteomics we monitored temporal changes in diGly site abundance in response to both proteasomal and translational inhibition, indicating both a dependence on ongoing translation to observe alterations in site abundance and distinct dynamics of individual modified lysines in response to proteasome inhibition. Further, we demonstrate that quantitative diGly proteomics can be utilized to identify substrates for cullin-RING ubiquitin ligases. Interrogation of the ubiquitinome allows for not only a quantitative assessment of alterations in protein homeostasis fidelity, but also identification of substrates for individual ubiquitin pathway enzymes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            An atlas of combinatorial transcriptional regulation in mouse and man.

            Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution. (c) 2010 Elsevier Inc. All rights reserved.
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              Tracking the ends: a dynamic protein network controls the fate of microtubule tips.

              Microtubule plus-end tracking proteins (+TIPs) are a diverse group of evolutionarily conserved cellular factors that accumulate at the ends of growing microtubules. They form dynamic networks through the interaction of a limited set of protein modules, repeat sequences and linear motifs that bind to each other with moderate affinities. +TIPs regulate different aspects of cell architecture by controlling microtubule dynamics, microtubule interactions with cellular structures and signalling factors, and the forces that are exerted on microtubule networks.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                6 February 2018
                11 January 2018
                : 9
                : 10
                : 9177-9198
                Affiliations
                1 Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK
                2 Genome Damage and Stability Centre, University of Sussex, Brighton, Falmer, BN1 9RQ, UK
                3 Centre for Microvascular Research, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK
                4 Present 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
                5 Present address: Protein Crystallography Facility, Centre for Structural Biology, Flowers Building, Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK
                Author notes
                Correspondence to: Márta Korbonits, m.korbonits@ 123456qmul.ac.uk
                Article
                24183
                10.18632/oncotarget.24183
                5823669
                29507682
                87e8de66-4611-49dd-9c39-d88864109a00
                Copyright: © 2018 Hernández-Ramírez et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 May 2017
                : 1 January 2018
                Categories
                Research Paper

                Oncology & Radiotherapy
                aip,co-chaperone,quantitative mass spectrometry,acromegaly,fipa
                Oncology & Radiotherapy
                aip, co-chaperone, quantitative mass spectrometry, acromegaly, fipa

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