Publikationsserver der Universitätsbibliothek Marburg
Titel:Galectin-3: Endozytose und Recycling in polaren Epithelzellen sowie seine Rolle im klarzelligen Nierenzellkarzinom
Autor:Straube, Tamara
Weitere Beteiligte: Jacob, Ralf (Prof.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0165
URN: urn:nbn:de:hebis:04-z2014-01652
DOI: https://doi.org/10.17192/z2014.0165
DDC: Medizin
Titel (trans.):Galectin-3: Endocytosis and recycling in polar epithelial cells and its role in clear cell renal cell carcinoma
Publikationsdatum:2014-08-07
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
endocytosis, Galectin-3, klarzelliges Nierenzellkarzinom, clear cell renal cell carcinoma, recycling, Endocytose, Epithelzelle, polar epithelial cell, Recycling, Galectin-3

Zusammenfassung:
Polare Epithelzellen stellen die Voraussetzung für ein funktionierendes Organ, wie z.B die Niere, dar. Sie bilden ein Monolayer an der Organaußenseite, das als Barriere gegen die Umwelt fungiert aber auch als Austauschsystem mit der Umwelt dient. Die polarisierte Struktur einer Epithelzelle ist durch eine apikale und basolaterale Membrandomäne charakterisiert. Diese Domänen sind durch tight-junctions voneinander separiert und unterscheiden sich in ihrer Lipid- und Proteinzusammensetzung. Die Polarität der Zelle wird durch einen gerichteten Transport von Lipiden und Proteinen aufrechterhalten. Im apikalen Proteintransport existieren zwei Transportwege, die sich aufgrund der Affinität der darin transportierten Proteine zu lipid rafts in einen raft abhängigen und einen raft unabhängigen Transportweg untergliedern lassen. Die Trennung der Transportwege erfolgt in einem post-Golgi Kompartiment und beruht auf der Ausbildung hochmolekularer cluster, vermittelt durch den Sortierrezeptor Galectin-3. Galectin-3 ist ein Galactose bindendes Lectin und fungiert als apikale Sortierplattform für raft unabhängige Glykoproteine. Es ist nicht nur intrazellulär präsent, sondern wird auch über einen unkonventionellen Sekretionsweg in den Extrazellulärraum transportiert. Von dort kann es vermutlich erneut in die Zelle aufgenommen werden wobei der Endozytosemechanismus noch ungeklärt ist. In der vorliegenden Arbeit konnte zunächst mit Hilfe von biochemischen Analysen ein Rezyklierungsprozess von endozytiertem rekombinantem Galectin-3 beobachtet werden. Mit Hilfe von TGN-Exit Analysen und anschließender DRM-Isolation konnte gezeigt werden, dass Galectin-3 60 min nach TGN-Block im Extrazellulärraum vorliegt und bei Wiederaufnahme in die Zelle mit lipid rafts assoziiert. Ergebnisse der hochauflösenden Mikroskopie und die Verwendung eines lipid raft Inhibitors bestätigen eine lipid raft abhängige Endozytose von Galectin-3. Desweiteren konnten Hinweise darauf gewonnen werden, dass die Bindung von Galectin-3 an Zuckerreste auf der Zelloberfläche eine entscheidende Rolle bei der Internalisierung spielt. Zudem konnte gezeigt werden, dass die Assoziation mit lipid rafts und die Internalisierung des Lectins pH-abhängig erfolgen. Während seines Rezyklierungsprozesses passiert Galectin-3 mit seinen gebunden Liganden verschiedene endosomale Kompartimente mit unterschiedlichen pH-Werten. In der vorliegenden Arbeit konnten erste Hinweise auf den Einfluss des pH-Wertes während des apikalen Proteintransportes des Neurotrophinrezeptors p75 und des Glykoproteins gp80 gesammelt werden. Zugleich konnten Anzeichen für eine pH-Abhängigkeit der durch Galectin-3 induzierten Bildung hochmolekularer cluster ermittelt werden. Neben seiner Funktion als apikaler Sortierrezeptor ist Galectin-3 an zahlreichen weiteren zellulären Prozessen wie der Regulierung des Zellzyklus, der Zell-Zell- Adhäsion, der Apoptose und Angiogenese beteiligt. Aufgrund dieser Funktionen spielt es eine wichtige Rolle während der Tumorgenese in Nierenzellen. Unter Verwendung konfokaler Fluoreszenzmikroskopie von humanem Nierengewebe und klarzelligem Nierenzellkarzinomgewebe konnte Aufschluss über die Lokalisation von Galectin-3 sowie verschiedener apikaler und basolateraler Markerproteine gewonnen werden. Galectin-3 konnte im gesunden Nierengewebe in einzelnen Epithelzellen des distalen Tubulus und Sammelrohres lokalisiert werden. Im Tumorgewebe zeigt es eine diffusere Verteilung und ist vermehrt im Zellkern zu beobachten. Mit Hilfe biochemischer Analysen konnte festgestellt werden, dass die Expression des Lectins bei 75% der untersuchten Patienten im klarzelligem Nierenzellkarzinom im Vergleich zum normalen Gewebe ansteigt. Dieser Expressionsanstieg korreliert während der Tumordifferenzierung mit dem Rückgang der Expression des Zell-Zell-Adhäsionmoleküls CEACAM1. Desweiteren konnten Interaktionspartner des Lectins während der Tumordifferenzierung mittels Galectin-3-Affinitätssäule identifiziert werden.

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