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Endocrine Abstracts (2005) 9 P148

BES2005 Poster Presentations Thyroid (33 abstracts)

Gene regulation by the c-terminal pxxp motif of pituitary tumor transforming gene (PTTG)

C Gokce , LA Tannahill , AL Stratford , FL Khanim , HN Pemberton , DS Kim , NJL Gittoes , K Boelaert , JA Franklyn & CJ McCabe

Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.

PTTG is tumourigenic in vivo and transactivates fibroblast growth factor-2 (FGF-2). We have previously identified expression of PTTG and FGF-2 as potential prognostic indicators for differentiated thyroid cancer. Critical to PTTG function is a double PXXP motif, forming a putative SH3-interacting domain. We employed cDNA array approaches to identify further genes regulated via this region. MCF12A cells were transiently transfected with vector-only (VO) control, wild-type (WT)-PTTG and a mutant abrogating PTTG's SH3-interacting domain (SH3-), and array analyses performed. Following transfection with WT plasmid, the associated molecule with the SH3 domain of STAM (AMSH) and somatostatin receptor-2 (SSTR2) mRNAs were induced 9.6 and 164 fold. AMSH plays a critical role in cytokine-mediated intracellular signalling downstream of the jak/jak2-STAM complex, binding STAM through a double PXXP motif similar to PTTG's. Somatostatin exerts an antiproliferative action via high-affinity membrane receptors including SSTR2. We validated our cDNA array findings through TaqMan RT-PCR, which confirmed that both SSTR2 and AMSH were induced by PTTG. Interestingly, AMSH expression was unchanged by expression of the SH3- mutation (0.97-fold, N=4, P=NS), but SSTR2 was increased (1.58-fold, N=4, P<0.05). As PTTG is raised in thyroid cancer, we examined AMSH and SSTR2 mRNA expression in 33 differentiated thyroid cancers and 7 normal thyroid samples. AMSH mRNA was reduced (41%, P<0.001) in cancers, with those demonstrating nodal involvement (N = 8) showing significantly lower AMSH mRNA expression than those without (N =13; P <0.05). SSTR2 mRNA was significantly increased in cancers (4.2-fold, P<0.05), with metastatic tumours (N = 4) showing higher expression than non-metastatic cancers (N = 15; P <0.05). Immunohistochemical analysis confirmed SSTR2 protein expression in normal and cancerous specimens. We suggest that signal transduction via the AMSH/STAM and SSTR pathways may be important in thyroid tumorigenesis, and that these pathways may be modulated via interaction with PTTG.

Volume 9

24th Joint Meeting of the British Endocrine Societies

British Endocrine Societies 

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