<p>In the recent years considerable progress has been made to understand how the protein Bcl-2 regulates apoptosis at the mitochondria. By comparison, the cell death mechanisms at the endoplasmic reticulum remain unclear. In response to the agents that cause endoplasmic reticulum stress in breast cancer cells, the cell-cell adhesion molecule E-cadherin is modified by two independent modifications comprising pro-region retention and O-glycosylation. Both the modifications on E-cadherin inhibit its cell surface transport and the resultant loss of E-cadherin on the plasma membrane sensitizes cells to apoptosis. During this process binding of E-cadherin to type I gamma phosphatidylinositol phosphate kinase (PIPKIγ), a protein required for E-cadherin trafficking to the plasma membrane is prevented by O-glycosylation. E-cadherin deletion mutants that cannot be O-GlcNAcylated continue to bind PIPKIγ, traffick to the cell surface and delay apoptosis, confirming the biological significance of the modifications and PIPKIγ binding in the cell death regulation. These results also led me to determine whether there is a cell death pathway in which commitment to cell death is mediated by proteins primarily located at the endoplasmic reticulum. The studies show that the growth of estrogen receptor-positive breast cancer cells in charcoal stripped bovine serum leads to a form of programmed cell death which is protected by Bcl-2 exclusively localized at the endoplasmic reticulum instead of the mitochondria. Interestingly, the BH3 mimetic ABT-737 can abolish the protection mediated by Bcl-2 localized at the endoplasmic reticulum. Taken together, these studies suggest the novel role of the endoplasmic reticulum in programmed cell death through the identification and elucidation of the mechanisms that regulate the cell death pathway at this organelle.</p> / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/12808 |
| Date | 04 1900 |
| Creators | Geng, Fei |
| Contributors | Andrews, David W., Leber, Brian, Doble, Brad, Biochemistry |
| Source Sets | McMaster University |
| Detected Language | English |
| Type | thesis |
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