Novel modulation of p53 activity in thyroid cancer

Seed, Robert Ian (2013). Novel modulation of p53 activity in thyroid cancer. University of Birmingham. Ph.D.

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Abstract

Thyroid cancer is responsible for more deaths than all other endocrine cancers combined, and its incidence is rising. In contrast to other cancers, thyroid carcinomas rarely display mutations in p53. p53 is a potent tumour suppressor, and serves to inhibit cell transformation. Interestingly, the thyroid gland is also sensitive to the effects of ionising radiation, where WT p53 would normally play a protective role. However, there is evidence to suggest that aberrant expression of cellular oncogenes can result in the functional inactivation of WT p53. PBF is a proto-oncogene found to be overexpressed in thyroid tumours. PBF overexpression causes transformation in vitro and tumourigenesis in vivo. Work within this thesis describes the functional relationship between PBF and p53 in thyroid cancer. We provide evidence for a direct interaction between PBF and p53 in thyroid cancer cells, and our data demonstrate that oncogenic expression of PBF adversely affects p53 homeostasis by increasing its degradation, with PBF potentially serving as a co-factor in a complex with p53 and HDM2. Surprisingly, PBF had no effect on p53-mediated transcription using focused microarrays. Nonetheless, overexpression of PBF conferred a significant survival advantage following DNA damage, indicating that PBF might potentially facilitate neoplastic growth and tumourigenesis. Besides regulation of transcription, p53 performs a wide range of biological functions. PBF may therefore serve to promote p53 inactivation independently of its role as a transcription factor. Overall, these data indicate that oncogenic expression of PBF may result in a novel mechanism of p53 inactivation, where PBF binds to p53 and accelerates its degradation in complex with HDM2. These events cause an increase in cell survival following DNA damage, thereby potentially promoting tumourigenesis in thyroid cancers expressing WT p53.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):