SFEBES2008 Poster Presentations Endocrine tumours and neoplasia (31 abstracts)
AIP: a protein mutated in familial acromegaly plays a role in the regulation of cell proliferation and shows cell-type specific subcellular localisation
Chrysanthia A Leontiou 1 , Maria Gueorguiev 1 , Sevda Hassan 1 , Jacqueline van der Spuy 2 , Francesca Lolli 1 , Maria Stolbrink 3 , Helen Christian 3 , Jennifer Wray 4 , David Bishop-Bailey 4 , Dan M Berney 5 , Lawrence A Frohman 6 , Paul J Chapple 1 , Ashley B Grossman 1 & Marta Korbonits 1
1Endocrinology, Barts and the London Medical School, London, UK; 2Division of Molecular and Cellular Neuroscience, Institute of Ophthalmology, University College London, London, UK; 3Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; 4Cardiac, Vascular and Inflammation Research, Barts and the London Medical School, London, UK; 5Histopathology, Barts and the London Medical School, London, UK; 6Section of Endocrinology, University of Illinois at Chicago, Chicago, Illinois, USA.
Mutations in AIP have been identified in a significant proportion of families with pituitary adenomas, most commonly in familial acromegaly. However, no data are available about the pituitary expression of AIP and how lack of AIP is involved in tumorigenesis.
We identified 10 kindreds with AIP mutations out of 31 families. We studied RNA and protein expression of AIP in normal as well as familial and sporadic pituitary adenomas. In the normal pituitary strong, AIP-GH and AIP-PRL double immunofluorescence-staining was present in somatotroph and lactotroph cells, specifically in the secretory granules, but with no detectable staining in any other cell types (ACTH, TSH and LH/FSH) or in familial adenomas. Expression studies in the sporadic pituitary adenomas, however, showed unexpected results. AIP is expressed not just in GH and prolactin-secreting adenomas but also in adenomas of corticotroph and gonadotroph origin. In addition, the subcellular localisation of AIP was different: in GH-adenomas AIP showed a secretory vesicular localisation (as in normal GH-cells), while in prolactin, ACTH and gonadotroph-adenomas it showed a cytoplasmic localisation, suggesting aberrant trafficking of the molecule within the cell.
We created mutant AIP plasmids based on the mutations of our kindreds. Over-expression of pCI-neo-AIP-plasmid in HEK293 and GH3 cells resulted in a significant reduction of cell proliferation: 46±5 and 71±3% of empty vector control. We overexpressed AIP in primary human fibroblasts with a retroviral vector and this also resulted in a significant reduction of cell proliferation (>50% day 1–9). In all the three cell types, the mutated AIP fail to inhibit cell proliferation.
We showed that AIP has specific expression in the GH and PRL secretory granules in the normal pituitary, but widespread cytoplasmic expression occurs in sporadic pituitary adenomas with mislocalisation of the AIP protein in non-GH adenomas. Our functional data suggest that AIP reduces cell proliferation and the mutations we have identified disrupt this effect.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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