Dokument

Zusammenfassung:
Galectin-3 ist ein Vertreter der Galectine, welche durch ihre Bindungsaffinität an β-Galactoside gekennzeichnet sind. Speziell Galectin-3 ist durch seinen chimären Aufbau, bestehend aus N-terminaler Oligomerisierungsdomäne, der C-terminalen Kohlenhydrat-Binderegion, und seinem ubiquitären Vorkommen im adulten Gewebe gekennzeichnet. Abhängig vom Zelltyp oder dem Proliferationsstadium ist es vermehrt extrazellulär, im Zytoplasma oder im Zellkern zu finden. Diese diffuse Verteilung führt auch zu einer Vielzahl an Funktionen für Galectin-3, die bisher noch nicht ausreichend aufgeklärt sind. Die subzelluläre Verteilung ist auch in verschiedenen Tumorvarianten sehr unterschiedlich. In Zellen des klarzelligen Nierentumors wird das Lektin verstärkt in den Zell-kern transportiert. Basierend auf dieser Beobachtung stellte sich die Frage nach möglichen Galec-tin-3-Interaktionspartnern im Zellkern und der Funktion dieser Interaktion. Im Rahmen dieser Arbeit wurde zunächst hnRNPA2B1 als Interaktionspartner von Galectin-3 identi-fiziert. Es konnte mittels biochemischer Methoden nachgewiesen werden, dass diese Interaktion Laktose-abhängig und RNA-unabhängig ist. Außerdem wurde die Interaktion mit Hilfe des Proximi-ty Ligation Assay bestätigt. Weitere mikroskopische Untersuchungen zeigten nukleäre Kolokalisa-tionen in punktförmigen Strukturen. Anhand einer Affinitätschromatographie konnte nicht nur die Interaktion zum hnRNPA2B1 identifiziert werden, es wurden auch weitere Interaktionspartner von Galectin-3 gefunden, wie die Spleißkomponenten U2AF65 oder U1 70k. In zusätzlichen Experimenten konnte gezeigt werden, dass Galectin-3 an der Prozessierung von mRNA beteiligt ist, da es nach gemeinsamer Depletion von Galectin-3 und Galectin-1 zur Akkumula-tion von mRNA im Zellkern kam. Darüber hinaus wurde durch RNA-Sequenzierung nach Galectin-3 knockdown demonstriert, dass das Lektin das alternative Spleißen einzelner Gene beeinflusst. Diese Beobachtungen werden durch die hier identifizierten Galectin-3-Interaktionspartner unter-stützt, da es sich dabei um Komponenten des alternativen Spleißapparates handelt.

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