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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