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Hexokinase 1 attenuates type II death receptor-induced apoptosis Open Access


Other title
cell viability
Type of item
Degree grantor
University of Alberta
Author or creator
Schindler, Anja
Supervisor and department
Foley, Edan (Medical Microbiology and Immunology)
Examining committee member and department
Kane, Kevin (Medical Microbiology and Immunology)
Goping, Ing-Swie (Cell Biology)
Screaton, Robert (Children's Hospital of Eastern Ontario, Ottawa)
Barry, Michele (Medical Microbiology and Immunology)
Department of Medical Microbiology and Immunology
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Deregulated TNF signaling with elevated or decreased levels of TNF-induced apoptosis causes numerous inflammatory and cancerous diseases. Thus, there is a clear need to identify cellular proteins that regulate cell fate in the presence of TNF. RNA interference technology provides an excellent tool to address that problem. It allows the rapid generation of transient protein depletion “mutants” in cell culture, whose behaviour in the context of TNF can be examined. I developed a quantitative high-throughput siRNA assay to identify modifiers of TNF-induced cell death in HeLa cells and screened a set of nine hundred eighty six proteins, which includes the entire set of human kinases and phosphatases and several of their binding partners or related proteins. Of all gene products tested, loss of hexokinase 1 (HK1) resulted in the greatest elevation in TNF-induced death. In secondary assays, I demonstrated that the presence of HK1 attenuates TNF-induced apoptosis. Specifically, HK1 attenuates the processing of key caspases and caspase substrates, and decrease of the mitochondrial membrane potential. The predominantly mitochondrial localization of HK1 prompted me to examine whether HK1 impacted TNF-induced apoptosis at the mitochondria. I found that HK1 constitutively stabilized the mitochondrial membrane potential at least in part through the inhibition of the pro-apoptotic Bcl-2 effector proteins Bax and Bak. In line with these findings, HK1 attenuated Bax translocalization and oligomerization to and at the mitochondria in the absence and presence of an apoptotic stimulus. Finally, I found that attachment of hexokinases to the mitochondria is a prerequisite for mitochondrial integrity and essential for pro-survival functions of hexokinases in TNF-induced apoptosis. These data are the first loss-of-function reports to examine the involvement of HK1 in the transduction of extrinsic apoptotic cues and identify HK1 as a potential target in deregulated TNF signaling.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Tumor necrosis factor alpha (TNF-alpha) signals through NF-kappaB, JNK, and caspase modules to drive physiological responses that range from inflammation to apoptosis. The balance between the individual modules determines the nature of the response, and deregulated TNF signaling has been implicated in numerous pathological conditions. We used a quantitative high-throughput RNA interference assay to probe the entire complement of human kinases and phosphatases for gene products that tilt the balance of TNF signal transduction in favor of cell death or cell viability. Of all gene products tested, loss of hexokinase 1 resulted in the greatest elevations in TNF-dependent death. In secondary assays, we demonstrated that hexokinase 1 does not alter TNF-dependent activation of NF-kappaB or JNK modules. Instead, hexokinase 1 modifies the induction of caspase-driven cell death. Specifically, we showed that hexokinase 1 inhibits the formation of active, pro-apoptotic caspases in response to extrinsic inducers of apoptosis. These data are the first loss-of-function reports to examine the involvement of hexokinase 1 in the transduction of cell death signals and indicate that hexokinases are critical determinants of the viability of cells in response to extrinsic apoptotic cues.

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