Publikationsserver der Universitätsbibliothek Marburg
Titel:"Charakterisierung transkriptioneller und nicht-transkriptioneller Funktionen der Faktoren Miz1 und c-Myc in der UVB-induzierten DNA-Schadensantwort" und "Die Inhibition der Miz1-Funktion durch den Tumorsuppressor Arf führt zum Verlust der Zelladhäsion und induziert Apoptose"
Autor:Herkert, Barbara
Weitere Beteiligte: Eilers, Martin (Prof.)
Veröffentlicht:2011
URI:https://archiv.ub.uni-marburg.de/diss/z2011/0238
DOI: https://doi.org/10.17192/z2011.0238
URN: urn:nbn:de:hebis:04-z2011-02389
DDC:500 Naturwissenschaften
Titel (trans.):"The Role of the Transcription Factors c-Myc and Miz1 in DNA Damage Response" and "The Tumor Suppressor Arf Induces Apoptosis via a Repressive c-Myc/Miz1 Complex"
Publikationsdatum:2011-03-04
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Myc, DNA damage, DNS-Schädigung, Myc, Miz1, Miz1, Arf, Apoptosis, Arf, Zelladhäsion, Apoptosis

Zusammenfassung:
Die onkogene Wirkung von c-Myc, die zur Entstehung eines breiten Spektrums maligner Tumore führt, wurde bisher hauptsächlich auf die Aktivierung von Zielgenen in einem Komplex mit Max zurückgeführt. Allerdings weisen aktuelle Studien auch auf eine bedeutende Rolle der Interaktion von c-Myc mit dem Transkriptionsfaktor Miz1 hin, die in einer transkriptionellen Repression resultiert. Daher beschäftigt sich diese Arbeit mit der Interferenz des c-Myc/Miz1-Komplexes mit der UVB-induzierten DNA-Schadensantwort sowie der Induktion der Apoptose durch den Tumorsuppressor Arf als Antwort auf onkogene Stimuli in Form erhöhter c-Myc-Mengen. Zunächst wurde durch Einsatz von murinen, embryonalen Fibroblasten, die eine Deletion der POZ-Domäne von Miz1 aufweisen, sowie durch die shRNA-vermittelte Depletion von Miz1 die Notwendigkeit von Miz1 als Aktivator der Cdkn1a Expression analysiert. Dabei konnte festgestellt werden, dass Miz1 in dem verwendeten Zellsystem keine essentielle Funktion als Transkriptionsaktivator des Zellzyklusregulators p21Cip1 einnimmt. In einem humanen Zellsystem konnte jedoch eine nicht-transkriptionelle Funktion von Miz1 in der ATR-abhängigen Signalkaskade identifiziert werden, die auf der Stabilisierung des Vermittlerproteins TopBP1 beruht und somit zur Aktivierung dieses Signalwegs führt. Diese Wirkungsweise von Miz1 basiert auf der Rekrutierung von TopBP1 zum Chromatin, was dieses vor der Ubiquitinierung durch die E3-Ligase HectH9 und dadurch vor dem proteasomalen Abbau schützt. Antagonisiert wird die stabilisierende Interaktion von Miz1 und TopBP1 durch c-Myc, dessen Überexpression die Dissoziation von TopBP1 vom Chromatin und dessen Abbau bewirkt. Dementsprechend blockieren erhöhte Mengen von c-Myc die Aktivierung der UVB-induzierten Signalkaskade und somit wahrscheinlich die Reparatur der vorliegenden Schäden. Darüber hinaus wurde die Bedeutung der Interferenz von Miz1, c-Myc und dem Tumorsuppressor Arf zum Schutz vor onkogener Transformation beschrieben. Diese potentiell tumorprotektive Wirkungsweise beruht auf der Ausbildung eines DNA-assoziierten, transkriptionell repressorischen c-Myc/Miz1/Arf-Komplexes. Die Inhibition der Transkription beinhaltet neben der Relokalisierung von Arf in das Nukleoplasma die Verdrängung des Koaktivators NPM von Miz1. Zudem konnte die Ausbildung von Heterochromatin in den Promotorbereichen der Zielgene nachgewiesen werden. Darüber hinaus induziert die Assoziation mit c-Myc und Arf die post-translationelle Modifikation von Miz1 durch das Ubiquitin-ähnliche Molekül SUMO. Da c-Myc die Sequenz eines hochkonservierten SUMO-Interaktionsmotifs (SIM) aufweist und in vitro SUMO-Spezies bindet, könnte sowohl die SUMOylierung von Miz1 als auch die Bindung des modifizierten Miz1-Proteins durch c-Myc an der Aufrechterhaltung des repressiven Chromatinstatus involviert sein. Neben dem Zellzyklusinhibitor P15INK4B reprimiert dieser Komplex eine Vielzahl von Genen, welche sowohl die Zell-Zell- als auch die Zell-Matrixadhäsion vermitteln. Daher führt die Expression von Miz1, c-Myc und Arf zum Verlust der Zelladhäsion und löst somit Anoikis aus. Da für die Ausbildung dieses repressiven Komplexes die Interaktion von Arf und Miz1 mit dem Transkriptionsfaktor c-Myc essentiell ist, liegt die Vermutung nahe, dass die Proteinmengen von c-Myc für den Wechsel von Seneszenz zu Apoptose entscheiden sind. Daher könnte diese Funktionsweise des c-Myc/Miz1-Komplexes eine Möglichkeit zur Eliminierung von Zellen mit onkogenen Mutationen darstellen.

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