Identification of components of the apoptosis (programmed cell death) pathways initiated by Fas and tumor necrosis factor.
dc.contributor.author | Tewari, Muneesh | |
dc.contributor.advisor | Dixit, Vishva M. | |
dc.date.accessioned | 2016-08-30T17:26:13Z | |
dc.date.available | 2016-08-30T17:26:13Z | |
dc.date.issued | 1995 | |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9722106 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/130378 | |
dc.description.abstract | Apoptosis, or programmed cell death, is a phenomenon that plays a fundamental role in a variety of biological processes, including embryogenesis and the regulation of the immune response. This dissertation explores the mechanism of apoptosis initiated by Fas and tumor necrosis factor (TNF) receptor, which are cytokine receptors that can initiate the cell death program. Apoptosis induced by either receptor was blocked by expression of CrmA, a cowpox virus-encoded serpin that inhibits interleukin-$1\beta$ converting enzyme (ICE). ICE is a cysteine protease bearing homology to CED-3, a nematode protease that is essential for apoptosis in Caenorhabditis elegans. A point mutant of CrmA lacking protease-inhibitory activity did not inhibit Fas or TNF induced apoptosis, indicating that a CrmA-inhibitable protease, either ICE or a related enzyme, is an obligatory component of the death mechanism. Further investigation identified a proteolytic substrate cleaved during Fas or TNF induced apoptosis: poly(ADP-ribose) polymerase (PARP). PARP cleavage to a signature 85 kDa fragment during apoptosis was blocked by expression of wild-type CrmA, but not by mutant CrmA. The fact that ICE itself cannot cleave PARP indicated the involvement of a similar but distinct cell death protease. A CED-3/ICE-like gene designated Yama was cloned and found to encode a protease zymogen that, upon activation, could cleave PARP to the apoptotic fragment and was inhibitable by CrmA. In addition, the 70 kDa component of the U1 small ribonucleoprotein (U1-70 kDa) was discovered to be a second proteolytic substrate cleaved during Fas and TNF induced apoptosis. Cleavage of U1-70 kDa occurred over a time course comparable to that of PARP and was likewise inhibited by CrmA but not by mutant CrmA, raising the possibility that Yama might be responsible for the cleavage. Finally, experiments described in this dissertation suggest that CrmA may function as a viral mechanism for evading immune surveillance, as expression of CrmA inhibited killing by cytotoxic T-lymphocytes. Taken together, the data establish the role of proteases as essential components of the mammalian cell death pathway. | |
dc.format.extent | 147 p. | |
dc.language | English | |
dc.language.iso | EN | |
dc.subject | Apoptosis | |
dc.subject | Ced-3 | |
dc.subject | Cell | |
dc.subject | Components | |
dc.subject | Crma | |
dc.subject | Death | |
dc.subject | Factor | |
dc.subject | Fas | |
dc.subject | Identification | |
dc.subject | Initiated | |
dc.subject | Necrosis | |
dc.subject | Parp | |
dc.subject | Pathways | |
dc.subject | Programmed | |
dc.subject | Tnf | |
dc.subject | Tumor | |
dc.title | Identification of components of the apoptosis (programmed cell death) pathways initiated by Fas and tumor necrosis factor. | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Biological Sciences | |
dc.description.thesisdegreediscipline | Cellular biology | |
dc.description.thesisdegreediscipline | Health and Environmental Sciences | |
dc.description.thesisdegreediscipline | Immunology | |
dc.description.thesisdegreediscipline | Molecular biology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/130378/2/9722106.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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