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Transcription of the p53 gene is stimulated by DNA damage. Newly synthesized p53 is translocated to the nucleus where it binds DNA and acts as a transcription factor to regulate gene transcription, suppress the cell cycle, and halt cellular proliferation. It has been hypothesized that cell cycle arrest allows time for the induction of repair genes. If the damage is extensive and the cell cannot repair itself, then cell death via p53-mediated apoptosis occurs. This is a protective mechanism to eliminate damaged and potentially cancerous cells. Therefore, normal p53 expression and function are essential whenever there is DNA damage. However, when p53 is damaged or mutated there is decreased repair time with no resulting apoptosis, thus permitting cells with damaged DNA to proliferate. This results in the tumorgenesis. This thesis tests the hypothesis that alterations in cellular copper (Cu) alter the ability of p53 to act as a transcription factor. This will be done by an experimental approach using the transient transfection of a p53- responsive reporter gene construct. Furthermore, we will report data suggesting that Cu toxicity induces the expression of p53 that has a mutant conformation. Macroarray technology was used to identify the genes that are induced by p53, and shows that a number of p53-regulated genes are differentially expressed in the presence and absence of Cu. In conclusion, the goal of this work is to not only understand the possible relationship between or toxicity, but also to understand the mechanisms that regulate the function of this important tumor suppressor protein.
A Thesis Submitted to the Department of Nutrition, Food and Exercise Sciences in Partial Fulfillment of the Requirement for the Degree of Master of Science.
Includes bibliographical references.
Florida State University
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