000286019 001__ 286019
000286019 005__ 20241018161650.0
000286019 020__ $$anot applicable
000286019 0247_ $$2URN$$a---
000286019 037__ $$aDKFZ-2023-02596
000286019 041__ $$aEnglish
000286019 1001_ $$0P:(DE-He78)d4c68225ca6cd393718be733a8e4097d$$aHänle-Kreidler, Simon$$b0$$gmale$$udkfz
000286019 245__ $$aCharacterization of novel substrates of SCF-FBXW7 in mitotic cell fate regulation$$f2018-10-01 - 2023-12-31
000286019 260__ $$aHeidelberg$$b---$$c2023
000286019 300__ $$a138
000286019 3367_ $$2DataCite$$aOutput Types/Dissertation
000286019 3367_ $$0PUB:(DE-HGF)3$$2PUB:(DE-HGF)$$aBook$$mbook
000286019 3367_ $$2ORCID$$aDISSERTATION
000286019 3367_ $$2BibTeX$$aPHDTHESIS
000286019 3367_ $$02$$2EndNote$$aThesis
000286019 3367_ $$0PUB:(DE-HGF)11$$2PUB:(DE-HGF)$$aDissertation / PhD Thesis$$bphd$$mphd$$s1702299450_20044
000286019 3367_ $$2DRIVER$$adoctoralThesis
000286019 4900_ $$aDissertation$$v--
000286019 500__ $$anot applicable
000286019 502__ $$aDissertation, Universität Heidelberg, 2023$$bDissertation$$cUniversität Heidelberg$$d2023$$gFakultät für Biowissenschaften$$o2023-02-21
000286019 520__ $$aProtein ubiquitylation is a post-translational modification, which can control various cellular processes. Ubiquitin is conjugated to a substrate by an enzymatic cascade comprising so-called ubiquitin writers: E1, E2 and E3 enzymes. More of the ubiquitin-code is continuously uncovered and functional relationships are established. The induction of proteasomal degradation is probably the most prominent function of protein ubiquitylation. The E3 ubiquitin ligases convey specificity by facilitating the substrate interaction. SKP1-CUL1-F-box protein complexes belong to the RING E3 ubiquitin ligases and are one of the largest groups of the over 600 human E3 ubiquitin ligases. Their substrate receptors, the F-box proteins, are interchangeable and they can therefore target a vast number of substrates. FBXW7 is one of the best characterized F-box proteins and acts as a tumor suppressor by targeting oncogenes like c-Myc, Cyclin E1 and NOTCH1 for degradation. Being the most frequently mutated F-box protein in human cancers, FBXW7 loss-of-function or deletion result in increased tumor proliferation and chemoresistance. FBXW7-deficiency promotes mitotic slippage in response to antimicrotubule drugs and the identification of FBXW7 substrates responsible for this phenotype remains a major task.In the presented thesis, I aimed at identifying novel substrates of FBXW7 which are involved in mitotic slippage to better understand mitotic cell fate regulation. Using a proteomics approach, I identified the Histone 3 lysine 4 methyltransferase complex component WDR5 as FBXW7 candidate substrates and showed that FBXW7 regulates WDR5 protein levels by ubiquitylation. I verified that FBXW7 and WDR5 interact in-vivo and in-vitro and found that the overexpression of WDR5 and Cyclin E1 can promote mitotic slippage. Reciprocally, the depletion of WDR5 and Cyclin E1 reduced mitotic slippage induced by knockdown of FBXW7 and significantly reduced polyploidization after mitotic slippage. Although the methyltransferase enzymatic subunit KMT2D is a substrate of FBXW7 and cooperates with WDR5, knockdown of KMT2D did not affect mitotic cell fate.Collectively, I identified WDR5 as a novel substrate of FBXW7 and showed that the FBXW7 substrates WDR5 and Cyclin E1 can promote mitotic slippage and are required for drug-induced polyploidy. My results help to better understand the mechanisms underlying chemotherapy resistance caused by treatment of cancers with antimicrotubule drugs.
000286019 536__ $$0G:(DE-HGF)POF4-316$$a316 - Infektionen, Entzündung und Krebs (POF4-316)$$cPOF4-316$$fPOF IV$$x0
000286019 8564_ $$u---
000286019 8564_ $$uhttps://inrepo02.dkfz.de/record/286019/files/20221123%20Simon%20H%C3%A4nle-Kreidler%20Thesis%20Final.pdf
000286019 8564_ $$uhttps://inrepo02.dkfz.de/record/286019/files/20221123%20Simon%20H%C3%A4nle-Kreidler%20Thesis%20Final.pdf?subformat=pdfa$$xpdfa
000286019 909CO $$ooai:inrepo02.dkfz.de:286019$$pVDB
000286019 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)d4c68225ca6cd393718be733a8e4097d$$aDeutsches Krebsforschungszentrum$$b0$$kDKFZ
000286019 9131_ $$0G:(DE-HGF)POF4-316$$1G:(DE-HGF)POF4-310$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lKrebsforschung$$vInfektionen, Entzündung und Krebs$$x0
000286019 9141_ $$y2023
000286019 9201_ $$0I:(DE-He78)F045-20160331$$kF045$$lF045 Zellzykluskontrolle und Carcinogenese$$x0
000286019 980__ $$aphd
000286019 980__ $$aVDB
000286019 980__ $$abook
000286019 980__ $$aI:(DE-He78)F045-20160331
000286019 980__ $$aUNRESTRICTED