p53 is rarely mutated in thyroid papillary carcinomas, despite the thyroid being highly sensitive to ionising radiation. The pituitary tumor transforming gene binding factor (PBF) is a proto-oncogene overexpressed in thyroid cancer. Oncogenic levels of PBF result in cell transformation in vitro and tumourigenesis in vivo. By serendipity we have found that PBF interacts directly with the tumour suppressor protein p53. In light of these data we have investigated the effects of oncogenic levels of PBF on p53 function. Co-immunoprecipitation assays confirmed direct binding of p53 in the intracellular environment. Subsequent overexpression of PBF at oncogenic levels resulted in a significant reduction in p53 half-life in thyroid papillary carcinoma cells (75 ± 2.5% decrease after 90 minutes, P<0.028, n=4). These findings correlated with increased ubiquitination of p53. Our preliminary data indicate that PBF co-localizes and interacts with the E3 ligase MDM2, a negative regulator of p53 function. Additionally we observed a significant reduction of cell viability in mock-transfected TPC-1 cells after treatment with gamma-irradiation compared to untreated controls (17.9 ± 0.008% decrease, P<0.016, n=4). Critically, overexpression of PBF abrogated this observed decrease of cell viability (0.2 ± 0.007% decrease, P=NS, n=4). Finally, murine thyroids overexpressing transgenic PBF displayed significantly higher levels of genetic instability than wild-type thyroids (18.75%, n=4). These findings highlight a novel mechanism of thyroid tumourigenesis whereby PBF binds to p53 and inhibits its function, resulting in increased cell survival after DNA damage in vitro, and significantly elevated genetic instability in vivo.