REGULATION OF CASPASE-8Apoptotic cell death is orchestrated by the activation and functions of caspases. The defined apoptoticpathways (and presumably others as well) involve the oligomerization of specific adapter molecules, that inturn bind and oligomerize apical, or initator, caspases. These cleave and activate executioner caspases thatthen cause the biochemical and morphological changes associated with apoptosis by cleaving specific proteinsubstrates in the cell. This component focuses on the activation, regulation, and function of theapical/initiator caspase-8 and its co-regulator FLIPL. Our central hypothesis on which the work is based isthat caspase-8 is a monoiner that can only be activated by its enforced dimerization. and not by proteolyticcleavage. The studies described herein will explore the structural elements of caspase-8 activation, either bymonomer-monomer association or through association with FLIPt. The regulation and function of theactivated caspase will be analyzed in detail. In the context of the Program Project, the activation and functionof caspase-8 is a key element in one of the two well-defined apoptotic pathways, the death receptor pathway,and probably in other lesser characterized pathways as well. With our changing understanding of themolecular activation of the initiator caspases, it is vital to explore how new views of caspase-8 activation andregulation affect our understanding of the function of this caspase in vivo.
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