Die Rolle der DNA-Bindungskooperativität für die p53-vermittelte Tumorsuppression im Lungentumor-Xenograft-Modell

p53 wird wegen seiner herausragenden Rolle als Tumorsuppressor auch als Wächter des Genoms bezeichnet: als Transkriptionsfaktor reguliert es die Expression zahlreicher Gene und nimmt hierdurch Einfluss auf die Zellproliferation. Bei zellulärem Stress, wie zum Beispiel bei DNA-Schädigung oder Akt...

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Bibliographic Details
Main Author: Brehm, Corinna Ulrike
Contributors: Stiewe, Thorsten (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Published: Philipps-Universität Marburg 2018
Online Access:PDF Full Text
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Table of Contents: p53 is known as the guardian of the genome due to its remarkable role as a tumor suppressor: as a transcription factor it regulates the expression of a multitude of genes, thereby influencing cell proliferation. Under cellular stress, such as after DNA-damage or activation of oncogenes, intracellular levels of p53 can rise quickly, leading to diverse reactions. These include transient cell cycle arrest, which allows DNA repair, senescence, an irreversible form of cell cycle arrest, and apoptosis, the programmed cell death. These mechanisms can inhibit cell proliferation and thus protect the organism against generation and proliferation of cancer cells. To date, the detailed mechanisms determining transient cell cylcle arrest, senescence or apoptosis remain to be elusive. p53 binds to the DNA as a tetramer in a cooperative manner, meaning that binding-strength of the whole p53-tetramer exceeds the sum of the binding strength of the four monomers. Binding stability between the four p53-molecules crucially influences target gene selection and correlates with apoptotic rates. The aim of this study was to investigate the influence of DNA-binding-cooperativity of p53 on its tumor suppressive capacity in vivo. p53-mutants with different cooperativity, ranging from extremely weak to strong, were transfected into a p53-negative lung tumor cell line. In a xenograft model it could be proven that higher DNA-binding-cooperativity leads to less tumor burden. Chemotherapy with doxorubicin additionally reduced tumor burden. These results underline a distinct dependency of tumor suppression and chemosensitivity of the tumor cells on the DNA-binding-cooperativity of p53. Interestingly, no constitutive activation of p53 was necessary, as a conditional activation of p53 only in the last week of treatment led to an equivalent effect. The gained insights into the effects of DNA-binding-cooperativity are of substantial relevance as substances which enhance cooperativity and thereby increase apoptosis rates could be potential drugs in cancer therapy. On the other hand, transient reduction of cooperativity in healthy bystander cells during chemotherapy could reduce side effects.