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The impact of GCN2 deletion on protein degradation in the liver during asparaginase exposure
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Burns, Jeffrey Baur. The impact of GCN2 deletion on protein degradation in the liver during asparaginase exposure. Retrieved from https://doi.org/doi:10.7282/t3-611k-b013

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TitleThe impact of GCN2 deletion on protein degradation in the liver during asparaginase exposure
NameBurns, Jeffrey Baur (author); Anthony, Tracy (chair); Dixon, Joseph (member); Reuhl, Kenneth (member); Guo, Grace (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-01 (degree)
SubjectToxicology, Chemotherapy, Lymphoblastic leukemia, Asparaginase, Autophagy, GCN2
Extent89 pages : illustrations
DescriptionAsparaginase is a biological chemotherapeutic used to treat acute lymphoblastic leukemia. A common side effect in patient populations is hepatotoxicity. Previously, our lab revealed that GCN2 plays an integral role in protecting the liver from these effects, and the absence of GCN2 leads to severe liver steatosis. The development of hepatic steatosis during asparaginase exposure was determined to be due to impaired triglyceride export which corresponded with reduced ApoB100 protein abundance. This thesis investigated the role of protein degradation in the loss of ApoB100 protein during asparaginase exposure. Wild type and GCN2KO mice were intraperitoneally-administered a single injection of asparaginase and then euthanized at various time points up to 24 hours post-exposure. At 6 hours post-exposure, transmission electron microscopy of liver sections suggested minimal autophagosome formation in the livers of mice exposed to asparaginase. However, biochemical markers of autophagy initiation and lysosomal degradation suggested that asparaginase promoted autophagy in a GCN2 dependent manner. Loss of GCN2 led to a decrease in markers of autophagy initiation, followed by an increase in markers for lysosomal degradation. The aberrant activation of mTORC1, resulting in increased inhibitory phosphorylation of ULK1, was also shown to influence this response, being largely GCN2 dependent during asparaginase stress. Finally, it was shown that core autophagy genes are decreased in GCN2KO mice exposed to asparaginase, whereas genes for ER stress and the ubiquitin-proteasome system were increased along with total protein ubiquitination. This thesis demonstrates a loss of GCN2 leads to a stalling of autophagy with an increased ER stress response after asparaginase exposure.
NoteM.S.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-611k-b013
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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