Die Rolle der DNA-Bindungskooperativität für die p53-vermittelte Tumorsuppression im Lungentumor-Xenograft-Modell
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Philipps-Universität Marburg
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Abstract
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.
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Created: 2018Issued: 2018-05-03Updated: 2018-05-03
Faculty
Medizin
Language
ger
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DoctoralThesis
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p53Tumorsuppression
DDC-Numbers
610
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Brehm, Corinna Ulrike: Die Rolle der DNA-Bindungskooperativität für die p53-vermittelte Tumorsuppression im Lungentumor-Xenograft-Modell. : Philipps-Universität Marburg 2018-05-03. DOI: https://doi.org/10.17192/z2018.0201.