The role of PTTG, PBF, p53 and MDM2 in thyroid cancer

Ryan, Gavin (2014). The role of PTTG, PBF, p53 and MDM2 in thyroid cancer. University of Birmingham. Ph.D.

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Abstract

Thyroid cancer is the most common endocrine malignancy and its incidence is increasing. p53, a potent tumour suppressor, is rarely mutated in thyroid cancer, and it therefore seems plausible there are other means of wild-type p53 inactivation. Overexpression of the human pituitary tumor-transforming gene, and its binding factor PBF, have been found in thyroid cancer. hPTTG1 is a multifunctional protein with roles in cell cycle control, DNA repair and apoptosis. It possesses a dual role in tumourigenesis, through initiation via increased instability and aneuploidy, and progression through induction of growth factors. Research performed in this thesis has characterised a thyroidal hPTTG1-Tg overexpressing mouse model, showing reduced thyroid size due to reduced cellular proliferation. Characterisation of Pttg1 knockout mouse thyroids showed growth factor expression dysregulation and potential senescence of thyroid cells. We identified no effect of hPTTG1 over or underexpression on goitre induction. PBF is a relatively uncharacterised protein, which is transforming in vitro and tumourigenic in vivo. PBF is capable of increasing p53 degradation via increased ubiquitination, and work in this thesis shows this is dependent on MDM2, an E3 ligase and primary regulator of p53. Furthermore interactions between PBF and MDM2 were demonstrated. We showed that PBF binds to the E3 ubiquitin ligase RAD6, which also ubiquitinaties p53, and regulates its expression. Taken together this work has identified critical and novel findings on the roles of hPTTG1 and PBF in thyroid cancer.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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