The ability of metazoan cells to undergo programmed cell death is vital to both the precise development and . long term survival of the mature adult. Cell deaths that result from engagement of the program result in apoptosis - the ordered dismantling of the cell that results in its """"""""silent"""""""" demise, coordinated by members of the caspase family of cysteine protease. Based on our initial discovery that the human protein X-linked lAP (XIAP) inhibits caspases-3 and -7, it is now clear that several caspases vital to the execution phase of apoptosis are under the regulation of distinct members of the lAP family. We hypothesize that lAPs set the threshold that must be exceeded for apoptosis to be executed, and that this may be a cell-specific mechanism for regulating the onset of the apoptotic catastrophe. The lAPs, are broadly distributed in organisms ranging from viruses to yeast to man. As their name indicates the founding members are capable of selectively blocking apoptosis, having initially been identified in baculoviruses. By now several of the viral, fly and mammalian lAPs have been demonstrated to inhibit caspases. But some cannot be caspase inhibitors, since yeast at least do not contain caspases. Therefore there are growing suggestions that lAPs may have functions other than caspase inhibition. In this application we propose to delineate the importance of key human lAPs to caspase regulation, and to investigate newly identified regulatory mechanism(s) of the lAPs themselves. Specifically, we hypothesize that: (1) lAPs function as built in regulators of the death pathway through their inhibition of caspases, and (2) specific modifications to lAPs control the functional amount of activity available for caspase regulation.
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