Distinct roles for the cellular inhibitors of apoptosis proteins 1 and 2

Apoptosis Research Centre, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H8L1, Canada.
Cell Death & Disease (Impact Factor: 5.01). 03/2011; 2(3):e135. DOI: 10.1038/cddis.2011.20
Source: PubMed


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    • "Given the high degree of homology between c-IAP1 and c-IAP2, it is not surprising that their functions have often been found to be redundant [42]. The best evidence for this comes from single c-IAP1- and c-IAP2-null mice, which despite the many pathways in which c-IAPs are involved are almost normal [1], [27], [28], whereas deficiency of both is embryonically lethal [7]. "
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    ABSTRACT: Cellular Inhibitors of Apoptosis 1 and 2 (c-IAP1 and c-IAP2) are ubiquitin protein ligases (E3s) that constitutively ubiquitinate and induce proteasomal-mediated degradation of NF-κB Inducing Kinase (NIK) and repress non-canonical NF-κB activation. Mice expressing an E3-inactive c-IAP2 mutant (c-IAP2(H570A)) have constitutive activation of non-canonical NF-κB, resulting in B cell hyperplasia and T cell costimulation-independence. If, and if so to what extent, c-IAP1 and c-IAP2 are redundant in NF-κB regulation in these mice is not known. Here we have generated mice expressing a mutant c-IAP1 that lacks E3 activity (c-IAP1(H582A)). These mice were phenotypically normal and did not have constitutive NF-κB activation in B cells or MEFs. siRNA-mediated knockdown of c-IAP2 showed that accumulated c-IAP2, resulting from lack of c-IAP1-dependent degradation, compensated for absent c-IAP1 E3 activity. Surprisingly, c-IAP1(H582A) T cells had a lower p100/p52 ratio than wild type T cells, and in the absence of costimulation proliferated to a degree intermediate between wild type and c-IAP2(H570A) T cells. Therefore, although c-IAP1 and c-IAP2 both can repress constitutive NF-κB activation, the relative importance of each varies according to cell type.
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