Scope of the Thesis
The proteasome is a protein complex mostly known for its role in the degradation of unneeded, damaged or misfolded proteins. The proteasome plays a central role in all cells and hence a widely studied protein assembly. Malfunctioning of this protein complex has major effects on cellular processes and is known to lead to the development of a variety of diseases such as cancer and neurodegenerative disorders. The proteasome is also an important target for drug discovery; for instance, proteasome inhibitors are used for the treatment of multiple myeloma. However, not much is known about the biological mechanisms behind these treatments. In this project we monitored the cellular responses in terms of protein abundance and protein ubiquitination dynamics upon proteasome malfunctioning (Chapter 3). In order to gain more insight into the specificity and function of individual proteasome complex components, we also manipulated single proteasome subunits, i.e., the proteasome-bound deubiquitinating enzymes (DUBs) and monitored the effects on the cellular (modified) proteome (Chapter 4). The proteasome is a key player in maintaining a balance in proteostasis under both normal and abnormal cellular conditions. In order to gain further knowledge about the functioning of the proteasome under such conditions we characterized the proteasome interactome under different stress conditions, such as oxidative stress, endoplasmatic reticulum stress and proteasome inhibition (Chapter 5). Large scale quantitative mass spectrometry is the central methodology applied in all studies described in this thesis. These types of global and unbiased approaches make it possible to study the relation of a protein complex with its direct cellular protein environment. In Chapter 6 we have monitored changes in the cellular environment upon activation of ecdysone-responsive genes, in terms of global transcriptome and global proteome dynamics, as well as in terms of ecdysone-receptor interactome dynamics. As such, this work provides several clues to address the relationship between mRNA and protein abundances in Drosophila.

Additional Metadata
Keywords Proteasome, ubiquitin, Quantitative Mass Spectrometry, SILAC, LFQ, protein degradation
Promotor C.P. Verrijzer (Peter) , J.A.A. Demmers (Jeroen)
Publisher Erasmus University Rotterdam
ISBN 978-94-93019-55-3
Persistent URL hdl.handle.net/1765/110280
Note For reasons of copyright there is a partial embargo for this dissertation
Citation
Sap, K.A. (2018, September 20). Dynamics of Protein Ubiquitination upon Proteasome Modulation : A Quantitative Mass Spectrometry Approach. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/110280


Additional Files
Cover-image-Sap.PNG Cover Image , 42kb
2_ch1_KSap.pdf Final Version , 1mb
3_scope_KSap.pdf Final Version , 132kb
4_ch2_KSap.pdf Final Version , 1mb
5_ch3_KSap.pdf Final Version , 2mb
8_ch6_KSap.pdf Final Version , 1mb
9_ch7_KSap.pdf Final Version , 349kb
10_appendix_KSap.pdf Final Version , 194kb
11_dankwoord_KSap_permanent_embargo.pdf Final Version , 119kb
_propositions_KSap.pdf , 55kb