Cell death is a normal feature of animal development. Studies on a number of cell types, such as neurons that die during formation of the animal nervous system and lymphocytes that die during receptor repertoire selection in adults, have shown that cells commonly kill themselves by activating built in suicide mechanisms. Cell deaths that result from engagement of the program result in apoptosis - the ordered dismantling of the cell that results in its silent demise, with packaged cell fragments removed by phagocytic cells. Though apoptosis is often studied within the context of normal development, even in mature animals programmed cell death plays important roles. For example, cell numbers are maintained by a balance between cell proliferation and cell death, with for instance, approximately 1011 neutrophils and 1010 colon epithelial cells turning over per day in humans. Morever, abundant evidence implicates dysregulation of programmed cell death in the pathogenesis of many diseases. Inappropriate increases in apoptotic cell death have been reported in AIDS, neurodegenerative disorders, and ischemic injury; whereas decreases in cell death contribute to cancer, autoimmune diseases, and possibly restenosis. The coordinated cellular demise is mediated by members of a family of cysteine proteases known as caspases whose activation follows characteristic apoptotic stimuli, and whose substrates include most of the proteins where limited cleavage produces the characteristic morphology of apoptosis. Not surprisingly, inhibition of caspases is a strategy adopted by viruses in their attempt to elude the apoptotic response of the cell to the infectious insult, however until now no natural human caspase inhibitors were known. We have recently discovered how members of a human protein family known as IAPs, previously recognized as inhibitors of apoptosis, function. In this grant proposal we present evidence that IAP family proteins are direct inhibitors of selected caspases. We hypothesize that IAPs function as built in regulators of the death pathway through their inhibition of caspases. We plan to test this hypothesis by determining 1) the inhibitory mechanism and specificity, 2) the range of apoptotic stimuli blocked by IAPs and specific mutant constructs, 3) the cellular location and pattern of expression; thereby detailing the functional role of the human IAP family proteins XIAP, cIAP-1, cIAP-2 and NAIP.
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