Publikationsserver der Universitätsbibliothek Marburg

Titel:Spindelcheckpoint-Inhibierung als neuer Therapieansatz in der molekularen Onkologie
Autor:Schneider, Verena Janina
Weitere Beteiligte: Bastians, Holger (Dr.)
Veröffentlicht:2010
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0173
DOI: https://doi.org/10.17192/z2010.0173
URN: urn:nbn:de:hebis:04-z2010-01732
DDC: Medizin
Titel (trans.):Pharmacological targeting of the mitotic spindle checkpoint - a novel strategy for anticancer therapy
Publikationsdatum:2010-03-15
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Mitose, Chemotherapy, Spindelcheckpoint, Spindlecheckpoint, Onkologie, Chemotherapie

Zusammenfassung:
Krebszellen sind charakterisiert durch die Deregulation des Zellzyklus und durch das Versagen von Zellzyklus-regulierenden Kontrollmechanismen, die auch als Checkpoints bezeichnet werden. Im Zentrum dieser Arbeit steht der Spindelcheckpoint, der die korrekte Aufteilung der Schwesterchromatiden auf die Tochterzellen in der Mitose kontrolliert. Die Funktion des Spindelcheckpoints ist in vielen Tumoren gestört und diese Funktionsstörung führt zu einer Resistenz der Tumoren gegenüber spindelschädigenden Chemotherapeutika. Der Inhibitor Gö6976, der in dieser Arbeit charakterisiert werden soll, ist in der Lage den Spindelcheckpoint zu inaktivieren und daher ist Gö6976 aus zwei verschiedenen Perspektiven heraus interessant. Zunächst ist ein spezifischer Inhibitor des Spindelcheckpoints von großem Nutzen für die Forschung als Instrument zur weiteren Aufklärung der Spindelcheckpoint-Signalkaskade. Andererseits könnte Gö6976 durch gezielte Hemmung des Spindelcheckpoints zur Entwicklung eines neuen Therapiekonzepts zur Behandlung chemotherapieresistenter Tumoren genutzt werden. Es konnte durch FACS-Analyse, Westernblot-Analyse und Chromosomen-Spreitung gezeigt werden, dass Gö6976 den Spindelcheckpoint inaktiviert. Die Untersuchungen ergaben, dass die Spindelcheckpoint-Inaktivierung durch Gö6976 von einem Proteasom-abhängigen Abbau der mitotischen Proteine Securin und Cyclin B begleitet wird. Weiterhin konnten folgende Phänotypen dem Inhibitor Gö6976 zugeordnet werden: Gö6976 beschleunigt den zeitlichen Ablauf der Mitose, induziert eine vorzeitige Trennung der Schwesterchromatiden („vorzeitige Anaphase“) und es wurden Chromosomen-Aufreihungsdefekte festgestellt. Interessanterweise konnte gezeigt werden, dass Gö6976 keine Multinuklei induziert, ein Phänotyp, der sonst häufig mit Spindelcheckpointdefekten assoziiert ist. Der Vergleich dieser Phänotypen mit denen, die durch Hemmung oder Reduktion der Proteinmengen von Spindelcheckpoint-Komponenten (Bub1, BubR1, Mad1, Mad2, Mps1 oder Aurora B) induziert werden, zeigt große Ähnlichkeiten. Weitere Experimente zur Identifikation des Zielmoleküls von Gö6976 wurden durchgeführt. In diesem Kontext wurde eine Dephosphorylierung von Bub1 und Mps1 beobachtet und es konnte gezeigt werden, dass Gö6976 zu einer Delokalisation der Checkpoint-Kinasen Bub1 und BubR1 vom Kinetochor führt.

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