The influence of PBF on p53 and Rad6 in thyroid cancer, and Oestrogen metabolism in colorectal cancer

Gilligan, Lorna Catherine (2012). The influence of PBF on p53 and Rad6 in thyroid cancer, and Oestrogen metabolism in colorectal cancer. University of Birmingham. M.Res.

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Abstract

PTTG binding factor (PBF) has been implicated in many cancers, including thyroid. One of the main treatments for thyroid cancer is ablation using Il3l. Previous research has shown PBF can inhibit Il3l uptake into the thyroid, which may account for some cancer recurrence. Unpublished data has shown PBF can bind to and inactivate p53, disrupt DNA repair, induce genetic instability and cause a twofold rise in the E2 ligase DNA repair protein Rad6. Rad6 is known to form a complex with p53 and aids regulation of p53 cellular levels. The aim of this project was to determine if PBF binds to and promotes Rad6 to impair DNA repair using siRNA, transfection, Western blotting and Co-Immunoprecipitation techniques. Results found that knock down of Rad6 lowered p53 levels and overexpressed Rad6 resulted in an abnormal Rad6-p53 co-localisation. Also, as PBF can induce Rad6, Rad6 can also induce PBF. In conclusion increased Rad6 expression resulted in an abnormal, perhaps oncogenic, interaction with p53, but it is still unknown if PBF binds to Rad6 inhibiting DNA repair capacity.

Colorectal cancer (CRC) is a worldwide problem which is often asymptomatic in the early stages leading to delayed diagnosis. Unfortunately advanced disease has no cure with treatment being palliative only. Evidence is accumulating that sex hormones can act both as a risk factor and propagate CRC tumour growth. However, current research examining the oestrogen metabolism pathway in CRC has revealed conflicting results. In an attempt to uncover what drives tumour growth the key oestrogen enzymes in both CRC cell lines and human tissue were investigated using LCA4S, FACS, RT-PCR, Western Blotting and radiolabelled STS activity assay. Results demonstrated that CRC cell line data
are extremely variable. Colo205 cells had greatest STS activity within CRC cell lines and in contrast to other studies oestradiol had no effect on apoptosis. In human female samples STS activity was increased in cancerous tissue compared to matched normal controls and this activity could be inhibited by STX64. In conclusion sex hormones are involved in the development and growth of colorectal cancer and STS inhibitors may benefit females with colorectal cancer.

Type of Work:

Thesis (Masters by Research > M.Res.)

Award Type:

Masters by Research > M.Res.

Supervisor(s):