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Identifying Essenti...
Identifying Essential Deubiquitinase Interactions and Targeting Protein Ubiquitination in Cancer
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- Gubat, Johannes, 1986- (author)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
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- D´arcy, Padraig, Associate Professor, 1978- (thesis advisor)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
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- Linder, Stig, Professor, 1954- (thesis advisor)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
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- Turkina, Maria, Associate Professor, 1973- (thesis advisor)
- Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten
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- Lindahl, Per, Professor (opponent)
- Department of Medical Biochemistry and Cell Biology, University of Gothenburg
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(creator_code:org_t)
- ISBN 9789180755603
- Linköping : Linköping University Electronic Press, 2024
- English 79 s.
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Series: Linköping University Medical Dissertations, 0345-0082 ; 1905
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Abstract
Subject headings
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- Cancer is the second leading cause of death globally and is one of the most pressing health issues today. While significant advances have been made in cancer treatment, drug resistance and toxicity remain formidable obstacles to successful therapy. Thus, there is a need to find novel targets that pave the way for new cancer therapeutics. Ubiquitination, the process of tagging substrate proteins with ubiquitin molecules, regulates many of the pathways that underlie cancer progression. This thesis aims to explore innovative strategies for combating cancer by focusing on crucial elements within the ubiquitination machinery, specifically the Ubiquitin-Proteasome System (UPS) and deubiquitinases (DUBs). In Paper I, we employed the Connectivity Map to discern UPS inhibitors by analyzing the gene expression patterns of various compounds in comparison to those induced by proteasome perturbation. In Paper II, we employed orthogonal methods to identify the primary mechanism for the cytotoxicity of b-AP15. Here, we showed that pharmacologic doses of b-AP15 resulted in strong proteasome inhibition and that cytotoxicity is mediated through the mitochondria and influenced by the proteasome-associated DUB, USP14. In Paper III, we explored the role of USP14 in colorectal cancer cells and evaluated its potential as a cancer target. We found that the genetic deletion of USP14 confers a quiescent phenotype to cancer cells. In Paper IV, we used CRISPR-based screens to search for new deubiquitinase targets. We identified deubiquitinase interactions essential for cancer and explored the possibility of combinatorial deubiquitinase targeting. We pinpointed highly-networked deubiquitinases (PSMD14, USP9X, USP39, and USP7) and deubiquitinase pairs represent promising drug targets. This thesis underscores the importance of the ubiquitination process in the search for novel cancer therapeutics and provides new avenues to explore in developing therapies based on the inhibition of deubiquitinases.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Cancer
- Deubiquitinase
- b-AP15
- Ubiquitin-proteasome system
Publication and Content Type
- vet (subject category)
- dok (subject category)
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Gubat, Johannes, ...
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D´arcy, Padraig, ...
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Linder, Stig, Pr ...
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Turkina, Maria, ...
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Lindahl, Per, Pr ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Linköping Univer ...
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