Activation of NF-κB by XIAP, the X Chromosome-linked Inhibitor of Apoptosis, in Endothelial Cells Involves TAK1

Abstract

Exposure of endothelial and many other cell types to tumor necrosis factor ␣ generates both apoptotic and anti-apoptotic signals. The anti-apoptotic pathway leads to activation of the transcription factor NF-B that regulates the expression of genes such as A20 or members of the IAP gene family that protect cells from tumor necrosis factor ␣-mediated apoptosis. In turn, some anti-apoptotic genes have been shown to modulate NF-B activity. Here we demonstrate that XIAP, a NF-Bdependent member of the IAP gene family, is a strong stimulator of NF-B. Expression of XIAP leads to increased nuclear translocation of the p65 subunit of NF-B via a novel signaling pathway that involves the mitogen-activated protein kinase kinase kinase TAK1. We show that TAK1 physically interacts with NIK and with IKK2, and both XIAP or active TAK1 can stimulate IKK2 kinase activity. Thus, XIAP may be part of a system of regulatory loops that balance a cell's response to environmental stimuli.

Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis

“…27,49 Enhanced apoptosis by downregulation of XIAP could partly be due to inhibition of NF-kB activity. 50,51 Overexpression of XIAP, a NF-kB-dependent member of IAP family lead to increased nuclear translocation of p65 subunit of NF-kB involving mitogen-activated protein kinase kinase (TAK1), via phosphorylation and sustained degradation of inhibitor (IkBa). 51 Moreover, an in -vitro ubiquitination assay identified XIAP as an ubiquitin-protein ligase for caspase-3.…”

“…50,51 Overexpression of XIAP, a NF-kB-dependent member of IAP family lead to increased nuclear translocation of p65 subunit of NF-kB involving mitogen-activated protein kinase kinase (TAK1), via phosphorylation and sustained degradation of inhibitor (IkBa). 51 Moreover, an in -vitro ubiquitination assay identified XIAP as an ubiquitin-protein ligase for caspase-3. 52 XIAP promoted ubiquitination and subsequent degradation of active caspase-3, but not of procaspase-3.…”

“…Thus, downregulation of XIAP may lead to decreased ubiquitin-protein ligase and NF-kB activity, resulting in increased sensitivity to apoptotic stimuli. 13,[50][51][52] Resistance to Apo2L/TRAIL was thus mediated by inhibition of both intrinsic and extrinsic apoptotic pathways. Compared to Apo2L/TRAIL, TNF-a ( a more potent inducer of NF-kB), may induce other antiapoptotic genes such as Bcl-X L and c-IAP-2, thus potentially counteracting the apoptotic signaling by TNF-a.…”

A highly conserved proapoptotic gene, IKIP, located next to the APAF1 gene locus, is regulated by p53

“…Expression vectors for flag-IKK2, HA-IKK1, MEKK1, NIK, TAK1, p38 and the 5xNF-kB-Luc reporter construct have been described previously. 27 The expression construct for p53 siRNA (pSUPER-p53) was obtained from OligoEngine (Seattle).…”

XIAP: Cell death regulation meets copper homeostasis

“…Acting as competitive inhibitors of caspase binding and through other mechanisms, these factors inhibit XIAP function, thereby facilitating propagation of the apoptotic cascade via the executioner caspases ( Figure 2). In addition to its anti-apoptotic properties, XIAP has also been implicated in a variety of intracellular signaling events including the NF-κB pathway [22,23], the c-Jun-N-terminal kinase pathway [24,25] and the TGF-β pathway [26][27][28].…”