The activation of death receptor Fas (CD95/APO1) triggers apoptosis inducing caspase activation by direct (extrinsic) and mitochondria dependent (intrinsic) pathways. Mitogen activated protein kinases (MAPK), which include p38, JNK and ERK kinases, are also activated during Fas signaling and are known to either positively or negatively regulate apoptosis. Chemical inhibition of JNK (SP600125) and p38 (PD169316) sensitize tumor cells to Fas mediated apoptosis. I studied Fas mediated apoptosis in Jurkat cells and in some experiments HeLa cells. PD169316 is less potent than SP600125 and attenuates the effect of the later when present together. PD169316 inhibits two isoforms of p38 which either promote (p38alpha) or inhibit (p38beta) apoptosis; I investigated their relative regulatory influences on Fas signaling. I show that p38alpha is essential for Fas mediated caspase-8 activation: it promotes the dephosphorylation and exclusion of c-FLIPS but not c-FLIPL from the death inducing signal complex (DISC). Distally both p38 isoforms positively influenced the intrinsic pathway by common and selective effects on pro-apoptotic Bcl-2 proteins. The sensitizing effects of p38 and JNK inhibition were ablated by Bcl-2 localized at the endoplasmic reticulum. In HeLa cells, the proapoptotic effects of p38alpha are overridden by the anti-apoptotic effects of ERK.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84082 |
| Date | January 2005 |
| Creators | Tourian, Leon |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002262073, proquestno: AAIMR22774, Theses scanned by UMI/ProQuest. |
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