The apoptotic pathway is a genetically conserved, energetic process that is essential for the development and homeostasis of organisms. Aberrant apoptosis, however, can result in variety of diseases including neurodegeneration and cancer. Apoptotic stimuli ultimately converge at the mitochondria, where cytochrome c is released into the cytosol to trigger formation of the apoptosome complex. The active apoptosome then goes on to activate the caspase family of proteases which cleave a myriad of substrates, resulting in cell death.
The core apoptotic components are ubiquitously expressed in cells, however some cell types (such as neurons and cancer cells) have an increased need to strictly regulate the apoptotic pathway. Unlike normal mitotic cells, postmitotic neurons have little regenerative potential and must often last the lifetime of the organism. Here, I identify novel ways in which neurons and cancer cells inhibit the apoptotic pathway at points downstream of cytochrome c. Specifically, I describe mechanisms by which postmitotic neurons of the PNS and CNS posttranslationally inactivate cytochrome c and Apaf-1, respectively, in order to ensure their longterm survival. In addition, my work suggests that cancer cells may use mechanisms similar to those adapted by neurons in order to evade apoptosis.
Despite a neuron's ability to inhibit programmed cell death, these cells must still be able engage the apoptotic pathway during development or in the event of extreme stress. Here, I uncover the mechanism by which cytochrome c becomes reactivated in sympathetic neurons during developmental apoptosis. In addition, I examine how XIAP's inhibition of caspases is overcome to allow neuronal apoptosis in response to DNA damage.
Together, these results not only illustrate the importance of a strict regulation of apoptosis in differentiating neurons, but also identify the mechanisms by which these blocks are overcome to allow death. I hope that a deeper knowledge of how the apoptotic pathway is reactivated in dying neurons could eventually lead to therapeutics to inhibit cell death in the context of neuronal pathologies, or to promote cell death in cancer.
|Commitee:||Baldwin, Albert, Cyr, Doug, Lamantia, Anthony, Milgram, Sharon|
|School:||The University of North Carolina at Chapel Hill|
|Department:||Cell & Developmental Biology|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 68/11, Dissertation Abstracts International|
|Subjects:||Neurology, Cellular biology|
|Keywords:||Apaf-1, Apoptosis, Cancer cells, Cerebellum, Neurons, Pentose phospate pathway, Postmitochondrial regulation, XIAP, p53|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be