xIAP Induces Cell-Cycle Arrest and Activates Nuclear Factor-κB

Abstract

Survival of human vascular endothelial cells depends on their ability to activate the transcription factor nuclear factor-kappaB (NF-kappaB), a regulator of antiapoptotic genes, such as the X chromosome-linked inhibitor of apoptosis protein (xIAP). In the present study, we demonstrated expression of xIAP in the endothelial lining of normal human arteries and veins and elevated levels in highly malignant human endothelial tumors. Using retroviral infection of human endothelial cells, we identified two novel survival mechanisms mediated by xIAP in endothelial cells. First, xIAP can activate the transcription factor NF-kappaB, a known survival factor for human endothelial cells. This positive feedback loop induced by xIAP is mediated via phosphorylation and sustained degradation of inhibitor (I) kappaBalpha. Second, xIAP can inhibit cell proliferation via downregulation of cyclins A and D1 and induction of the cyclin-dependent kinase inhibitors p21(Cip1/Waf1) and p27(Kip1). Cleavage of xIAP by caspases during endothelial cell apoptosis disables both of these biological functions of xIAP. Thus, caspase-mediated cleavage of xIAP interrupts a positive regulatory cytoprotective loop between NF-kappaB and xIAP and increases the vulnerability of the cell to apoptosis by releasing it from an xIAP-mediated quiescent state.

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.…”

“…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.…”

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

“…Both XIAP and c-IAP1 can be cleaved by caspases in vitro, [42][43][44] but the physiological significance is unknown. The proteolytic fragments of IAPs that are yielded by caspase processing may have retained or reduced caspaseinhibitory capacities, or may even have shifted toward proapoptotic activity in case of c-IAP1.…”

“…77,78 XIAP may also induce NF-kB signaling through activation of mitogen-activated protein kinases ( Figure 5). 44,79 Activation of NF-kB signaling induces expression of c-IAP1, c-IAP2 and XIAP. 77,78,80 This provides Regulatory mechanisms that control IAPs; regulating the regulators of apoptosis.…”

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].…”