The first reported mutations of the proto-oncogene pituitary tumor transforming gene 1 - binding factor (PBF); characterising their functional significance

[摘要] Pituitary tumor transforming gene1 (PTTG1) - binding factor (PBF) is a ubiquitously expressed transmembrane glycoprotein that is significantly upregulated in a variety of human tumours. In thyroid cancer, PBF is implicated in early tumour recurrence, distant metastasis and poor oncological outcome. Indeed, PBF induces cell transformation in vitro and tumourigenesis in vivo. PBF interacts with multiple protein-binding partners and modulates their activities and functions, including cortactin, Src, NIS and p53. According to the COSMIC and TCGA databases, 27 PBF mutations have now been reported in human cancer. The studies in this thesis aimed to establish the basic biochemical characteristics of the first 10 reported missense PBF mutations, including protein glycosylation, dimerisation and stability. Following initial functional studies, the impact of two in vivo mutations, C51R and R 140W, upon WT PBF function in modulating cellular proliferation, cell invasion, cell migration, radioiodine uptake and transforming ability were investigated in more depth. The data in this thesis demonstrate that although the reported mutations preserve some critical functions of PBF, it is unlikely that PBF mutations represent distinct driver events, and that upregulation of PBF expression in human cancer may be more important in terms of driving tumourigenesis than sequence changes.

[发布机构] University:University of Birmingham;Department:Institute of Metabolism and Systems Research

[关键词] R Medicine;RC Internal medicine;RC0254 Neoplasms. Tumors. Oncology (including Cancer)