Identification of Components of the Cell Death Pathway
Annual rept. 1 Jun 97-31 May 98
MICHIGAN UNIV HOSPITALS ANN ARBOR
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Transformed cells retain part or all their apoptotic machinery. Therefore, understanding the molecular details of this machinery is paramount for developing new anti cancer therapies that activate the cells own suicide program. The lab has focused initially on the identification of cell death components that are activated by the cell surface receptors FAS and TNFR- 1. This has led to identification of the Caspase cascade. Remarkably, the some members of the cascade are directly recruited to the receptors. The activation of the apical Caspase is the first enzymatic reaction during death receptor signaling and we show that this reaction is autocatalytic triggered by aggregation of the zymogen form of Caspase-8. We identified a protein homologous to Caspase-8 that inhibits auto-activation. It has no proteolytic activity and binds to Caspase-8 inhibiting receptor recruitment and hence auto-activation. Caspase-9 is another apical Caspase that is implicated to be activated by intracellular death stimuli and associates with Apaf- 1. We show that molecular interactions observed in C. elegans are conserved in mammalian cells. Caspase-9 forms a complex with Apaf-1 and Bcl-xL. This observation uncovers a potential mechanism for the Bcl-2 family of proteins.
- Anatomy and Physiology
- Medicine and Medical Research