Calpain 9 functions in TNF receptor mediated apoptosis

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Title: Calpain 9 functions in TNF receptor mediated apoptosis
Author: Kunkel, Gregory Thomas
Abstract: Evasion of apoptosis is a hallmark of cancer development . The Inhibitor of Apoptosis Proteins , IAPs , block Caspase activity and cell death . Release of the Second Mitochondria -Derived Activator of Caspases , Smac , from the mitochondria relieves IAP Caspase inhibition , activating apoptosis . Our lab has developed a small molecule Smac mimetic . Surprisingly , approximately 25 % of cell lines show single agent Smac mimetic sensitivity through activation of autocrine TNF -a secretion and TNF dependent apoptosis . Using Smac mimetic sensitivity as a model system , I performed a genome -wide high -throughput siRNA screen and identified Calpain 9 , CAPN9 , as a novel component of TNF -alpha induced apoptosis . CAPN9 knockdown does not affect TNF -a secretion , yet is essential for downstream activation . Two splice variants are reported for CAPN9 . The smaller splice , CAPN9 -SP2 , is required for effective TNF -a induced apoptosis . CAPN9 is essential for RIPK1 recruitment and ubiquitination at the TNFR1 upon activation with TNF -alpha . CAPN9 knockdown demonstrates previously unreported association of ubiquitinated proteins , and actin binding proteins with TNFR1 in the absence of stimulus . This interaction is CAPN9 dependent and correlates with CAPN9 regulation of TNF -a induced apoptosis . [Keywords : Calpain , SMAC , IAR , TNF , ubiquitin , RJPK1]
URI: http : / /hdl .handle .net /2152 .5 /1029
Date: 2012-07-20

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Calpain 9 functions in TNF receptor mediated apoptosis. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /1029 .

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