AIP reduces cAMP signalling and regulates GH secretion in GH3 cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 167-198-Hypothalamus-Pituitary Development & Biology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-198
Josanne Vassallo1, Robert Formosa*2 and Agela Xuereb-Anastasi3
1St Lukes Hospital, L-Ibragg, Malta, 2University of Malta, Qawra, Malta, 3University of Malta, Msida, Malta
Mutations in the aryl hydrocarbon receptor – interacting protein (AIP) gene are a relatively common occurrence in familial cases of pituitary adenomas, particularly those of sommatotroph and lactotroph origin (1,2). The AIP protein is a co-chaperone that has been found to interact with a number of proteins, including phosphodiesterases, G-proteins and a number of nuclear receptors. AIP has been demonstrated to act as a tumour suppressor in pituitary cells although the precise mechanism by which AIP protects these cells from neoplastic growth remains unknown.  Preliminary studies over-expressing AIP in GH3 cells have shown that wild-type AIP over-expression reduces forskolin-induced cAMP/CREB – driven transcription and intracellular cAMP levels while a non-functional AIP variant failed to do so. GH secretion was also similarly reduced by wild-type AIP over-expression. In an attempt to verify AIP’s role in regulating cAMP and GH in GH3 cells, knock down experiments were carried out. GH3 cells were transfected with rat Aip siRNA and cAMP – driven transcription was analysed using CRE – luciferase reporter assays and cAMP target gene quantification. Intracellular cAMP and secreted GH from GH3 cells was also measured. Finally co-transfection of Aip siRNA and wild-type AIP was carried out to analyse whether over-expressed human AIP could rescue the impact of endogenous rat Aip knock down. Results of endogenous Aip knock down resulted in a marked increase in cAMP – driven transcription and intracellular cAMP concentration. Co-transfection with human wild-type AIP managed to reverse the effects of Aip knock down and the effect on cAMP signalling. Interestingly, Aip knock down resulted in a reduction of GH secretion, possibly due to the direct interaction between AIP and GH in the secretory granules of sommatotroph cells. In conclusion, Aip was shown to inhibit cAMP signalling and regulate GH secretion, either through direct interaction with GH or by regulating intracellular cAMP levels.

1. Vierimaa O, Goergitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TML, Salmela PI, Paschke R et al. 2006 Pituitary Adenoma Predisposition Caused by Germline Mutations in the AIP Gene. Science 312 1128–1230.2. Leontiou CA, Gueorguiev M, van der Spuy J, Quinton R, Lolli F, Hassan S, Chahal HS, Igreja SC, Jordan S, Rowe J, et al. 2008 THE ROLE OF THE AIP GENE IN FAMILIAL AND SPORADIC PITUITARY ADENOMAS.  Journal of Clinical Endocrinology & Metabolism 93(6) 2390-401

Nothing to Disclose: JV, RF, AX

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Sources of Research Support: This research has been funded by the Malta Government Grant Scheme (Vote no. 88-019) and the University of Malta Research Fund Committee Allocation (Vote no. PHBRP07-01)
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