Publikationsserver der Universitätsbibliothek Marburg
Titel:Die Rolle der DNA-Bindungskooperativität für die p53-vermittelte Tumorsuppression im Lungentumor-Xenograft-Modell
Autor:Brehm, Corinna Ulrike
Weitere Beteiligte: Stiewe, Thorsten (Prof. Dr.)
Veröffentlicht:2018
URI:https://archiv.ub.uni-marburg.de/diss/z2018/0201
URN: urn:nbn:de:hebis:04-z2018-02013
DOI: https://doi.org/10.17192/z2018.0201
DDC: Medizin
Titel (trans.):The role of DNA-binding-cooperativity for p53-mediated tumor suppression lung tumor xenograft model
Publikationsdatum:2018-05-03
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
p53, Tumorsuppression

Zusammenfassung:
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 Aktivierung von Onkogenen, steigt der Spiegel von p53 in der Zelle rasch an. Mögliche Konsequenzen sind ein transienter Zellzyklusarrest, der eine DNAReparatur ermöglicht, die Seneszenz, ein irreversibler Zellzyklusarrest, oder die Apoptose, der programmierte Zelltod. Durch diese Maÿnahmen wird die Proliferation der Zelle vorerst gestoppt und der Organismus vor Generierung und Vermehrung von Krebszellen geschützt. Wie genau die Entscheidung zwischen transientem Zellzyklusarrest, Seneszenz und Apoptose getroffen wird, ist bis heute nicht abschließend geklärt. p53 bindet als Tetramer kooperativ an die DNA, was bedeutet, dass die Bindung des kompletten p53-Tetramers an die DNA stärker ist als die Summe der Bindungen der vier einzelnen p53-Monomere. Die Stabilität der Bindung zwischen den einzelnen p53-Molekülen beeinflusst die Auswahl der Target-Gene entscheidend und korreliert mit dem Ausmaÿ der induzierten Apoptose. Um den Einfluss der DNA-Bindungskooperativität von p53 auf die Tumorsuppression zu untersuchen, wurden in dieser Arbeit unterschiedlich stark kooperative p53-Mutanten stabil in eine p53-negative Lungenkarzinomzelllinie transfiziert. Im Lungentumor-Xenograft-Modell konnte gezeigt werden, dass sich bei höherer DNA-Bindungskooperativität von p53 signifikant weniger Tumore entwickeln. Eine zusätzliche Chemotherapie mit Doxorubicin vermochte die Tumormasse nochmals zu reduzieren. Diese Ergebnisse belegen eindrucksvoll die Abhängigkeit der Tumorsuppression sowie der Chemosensibilität von der DNA-Bindungskooperativität von p53. Interessanterweise war keine konstitutive Aktivität von p53 notwendig, sondern eine konditionelle Aktivierung ausschlieÿlich in der letzten Behandlungswoche führte zu einem gleichwertigen tumorsuppressiven Effekt. Dieses Wissen um die Effekte der DNA-Bindungskooperativität ist therapeutisch hoch interessant, da Substanzen, die die Kooperativität erhöhen und somit die Apoptoserate steigern, zur Behandlung von Tumorerkrankungen eingesetzt werden könnten. Alternativ könnte eine transiente Absenkung der Kooperativit ät der gesunden Körperzellen bei Chemotherapie die Nebenwirkungsrate senken.

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