The cardinal feature of apoptosis is the activation of a family of proteases termed caspases, and in some forms, loss of mitochondrial integrity and release of cytochrome c into the cytoplasm are viewed as necessary components of cell death. In receptor-mediated apoptosis, more specifically Somatostatin (SST) receptor (SSTR)- and Fas-signaled apoptosis, an additional feature is intracellular acidification (pHi) and Protein Tyrosine Phosphatase (PTP) activity. Increased translocation and activity of PTP, more specifically SHP-1 at the cell membrane as well as the functional activation of caspase-8 are required to reduce pHi. Also, a decrease in mitochondria) membrane potential (Deltapsim) and release of cytochrome c (cyt c) are concomitant with a decrease in pHi suggesting that mitochondrial dysfunction is a consequence and not a cause of acidification. Inhibition of caspase-8 activation and prevention of SHP-1 translocation abrogates the ability of SST to induce acidification and mitochondrial disruption, whereas inhibition of other caspases such as caspase-9, or -3/7 are ineffective. Protection from cell death can also be accomplished by Bcl-2. In this model, Bcl-2 elevates resting pHi and attenuates acidification and apoptosis only when the overexpressed Bcl-2 is targeted to the endoplasmic reticulum (ER) but not the mitochondria. In conclusion, we established that mitochondrial breakdown follows acidification and that acidification is dependent on caspase-8 and SHP-1 activation. Additionally, effector caspases are induced only when there is concomitant acidification. Bcl-2 cannot prevent acidification-dependent apoptosis at the level of the mitochondria despite protecting it revealing that mitochondrial disruption is a potentiating, but not essential event in the apoptotic pathway.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.30700 |
| Date | January 1999 |
| Creators | Martino, Giovanni. |
| Contributors | Srikant, C. B. (advisor) |
| 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: 001740671, proquestno: MQ64404, Theses scanned by UMI/ProQuest. |
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