Dokument

Zusammenfassung:
Während der Mitose werden die Schwesterchromatiden gleichmäßig auf zwei Tochterzellen verteilt, was für den Erhalt einer Euploidie essentiell ist. Eine chromosomale Instabilität, die fortwährende Fehlverteilung von Chromosomen, als Grundlage der Aneuploidie, ist jedoch ein Hauptkennzeichen von Tumorzellen. Dies deutet auf häufige Tumor-assoziierte Defekte in der Mitose hin. In der Tat wurde gezeigt,dass eine chromosomale Instabilität direkt zur Tumorgenese beitragen kann. Es ist dahervon größter Bedeutung, die molekularen Mechanismen der chromosomalen Instabilität zu verstehen und die Gene zu identifizieren, deren Veränderung zu einer aberranten Progression der Mitose beitragen. In unserer Arbeitsgruppe wurde CHK2 als ein Tumorsuppressorgen identifiziert, das für den Erhalt einer chromosomalen Stabilität essentiell ist und in meiner Arbeit habe ich eine neue mitotische Funktion von Chk2 charakterisiert. Die Chk2 Kinase, der zuvor eine Funktion im DNA-Beschädigungs-Signalweg zugeschrieben wurde, wird nicht nur nach einer DNA-Beschädigung, sondern auch während der Mitose aktiviert. Ich konnte zeigen, dass Chk2 für die normale Progression der Mitose und für die ordnungsgemäße Ausbildung einer mitotischen Spindel erforderlich ist. Eine Minderexpression oder der Verlust der Kinasefunktion von CHK2 führen zu Defekten in der Spindelstruktur, welche mit einer zeitlichen Verzögerung in der Prometaphase assoziiert sind. In Folge dieser transienten Spindeldefekte wird die Ausbildung von isolierten, sogenannten „lagging“ Chromosomen in der Anaphase, die nicht ordnungsgemäß auf die Tochterzellen segregiert werden können, gefördert. Sowohl das Auftreten dieser isolierten Chromosomen als auch die chromosomale Instabilität konnte durch eine ektopische Expression von MCAK, einer Mikrotubuli-Depolymerase, die eine zentrale Funktion bei der Korrektur fehlerhafter Anheftungen von Chromosomen an die mitotische Spindel erfüllt, unterdrückt werden. Bemerkenswerterweise werden diese nicht korrekt an die mitotische Spindel angehefteten Chromosomen, die durch den Verlust von CHK2 induziert werden, nicht von einem mitotischen Kontrollmechanismus, dem sogenannten Spindel-Kontrollpunkt, erkannt und tragen damit direkt zur Ausbildung der Aneuploidie bei. Meine Ergebnisse zeigen, dass Chk2 überraschenderweise eine zentrale Funktion bei der Ausbildung der mitotischen Spindel erfüllt, die eine Voraussetzung für die ordnungsgemäße Anheftung der Chromosomen und für den Erhalt der chromosomalen Stabilität darstellt. Somit könnte diese neue mitotische Funktion von Chk2 zu dessen Tumorsuppressor-Funktion beitragen, die bislang wenig verstanden ist. Neben ihrer fundamentalen Rolle für den Erhalt einer chromosomalen Stabilität stellt die Mitose eine wichtige Zielstruktur für die anti-Tumor Therapie dar. Anti-mitotisch wirksame Chemotherapeutika wie das Taxol und verschiedene Vinca-Alkaloide, die seit langem in der Klinik eingesetzt werden, binden an Mikrotubuli und hemmen die Spindeldynamik. Dies führt zu einer gestörten Chromosomen-Aufreihung, die der Spindel-Kontrollpunkt detektiert und in Folge die weitere mitotische Progression hemmt. Unsere Arbeitsgruppe konnte zeigen, dass der Spindel-Kontrollpunkt nicht nur eine zentrale Rolle zur Vermittlung des mitotischen Arrests, sondern auch für die Chemotherapie-aktivierte Apoptose spielt. Da Krebszellen häufig Fehlfunktionen des Spindel-Kontrollpunktes aufweisen, können diese somit sowohl zu Chromosomen- Fehlverteilungen als auch zu Chemotherapie-Resistenzen führen. Um solche Therapieresistenten Tumorzellen anzugreifen, könnte die in verschiedenen Maus- und Zellkulturmodellen gezeigte Essentialität des mitotischen Spindel-Kontrollpunktes als Grundlage eines neuen Therapiekonzeptes genutzt werden. Dabei könnte der Signalweg des Spindel-Kontrollpunktes direkt als Zielstruktur für die Tumor Therapie dienen. Unsere Arbeitsgruppe hat die Indolokarbazol-Verbindung Gö6976 als einen Inhibitor des Spindel-Kontrollpunktes identifiziert, der Apoptose in Tumorzellen induziert. In meiner Arbeit habe ich diesen pharmakologischen Inhibitor des Spindel-Kontrollpunktes charakterisiert. Dabei habe ich gezeigt, dass Gö6976 in vitro und in vivo die mitotischen Kinasen Aurora A und Aurora B hemmt. Die Hemmung von Aurora A durch Gö6976 verursacht dabei Defekte im Spindelaufbau und der Chromosomen-Aufreihung während die gleichzeitige Hemmung von Aurora B zu einer Aufhebung der Spindel-Kontrollpunk-Funktion führt, was schließlich den mitotischen Austritt der beschädigten Zelle bewirkt. Diese duale Hemmung zweier mitotischer Kinasen, die am Spindel-Kontrollpunkt beteiligt sind, führt letztendlich zu einer effizienten und Tumor-selektiven Induktion von Apoptose und dies erfolgt unabhängig von der Spindel-Kontrollpunkt-Aktivität. Daraus ergibt sich ein neues, vielversprechendes Therapie-Konzept, in dem der mitotische Spindel-Kontrollpunkt und seine assoziierten mitotischen Kinasen als neue Zielstruktur genutzt werden und in dem Resistenz-Mechanismen vermieden werden, die sich aufgrund von Fehlfunktionen des Spindel-Kontrollpunktes ergeben.

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