Identification of XAF1 as an antagonist of XIAP anti-Caspase activity

Abstract

The inhibitors of apoptosis (IAPs) suppress apoptosis through the inhibition of the caspase cascade and thus are key proteins in the control of cell death. Here we have isolated the protein XIAP-associated factor 1 (XAF1) on the basis of its ability to bind XIAP, a member of the IAP family. XIAP suppresses caspase activation and cell death in vitro, and XAF1 antagonizes these XIAP activities. Expression of XAF1 triggers a redistribution of XIAP from the cytosol to the nucleus. XAF1 is ubiquitously expressed in normal tissues, but is present at low or undetectable levels in many different cancer cell lines. Loss of control over apoptotic signalling is now recognized as a critical event in the development of cancer. Our results indicate that XAF1 may be important in mediating the apoptosis resistance of cancer cells.

Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL

“…Real-time RT-PCR (Table 1) and immunoblotting (data not shown) also identified cellspecific induction of XAF1 by IFNs, markedly in SK-MEL-28 but less in SK-MEL-3. XAF1 interacts with an inhibitor of apoptosis (XIAP) that may function as a competitive inhibitor of caspases to play a critical role in TRAIL-induced apoptosis (Deveraux et al, 1997;Liston et al, 2001;Leaman et al, 2002;Chawla-Sarkar et al, 2004). XAF1 has been silenced by DNA methylation in gastric cancer and is frequently reduced in expression in melanoma (Byun et al, 2003;Ng et al, 2004;Reu et al, 2006a).…”

Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via caspase-independent apoptosis

“…8 To explore whether XAF1 could sensitize tumor cells to ZD55-triggered death, SW620, A549, NHLF and HSMC were infected with Ad-XAF1, ZD55-EGFP, ZD55-XAF1 or ONYX-015 at various MOIs as indicated. Cells were stained with crystal violet 7 days later.…”

“…Overexpression of XAF1 does not appear to induce apoptosis, 8 while previous studies have shown that overexpression of XAF1 could sensitize cancer cells to the proapoptotic effects of etoposide and tumour-necrosis factor-related apoptosis-inducing ligand (TRAIL). 8,14 Recently, it was reported that XAF1 can cooperate with tumor necrosis factor a (TNFa) in the induction of apoptosis.…”

“…It was reported to directly antagonize the anticaspase activity of XIAP or trigger a nuclear translocation of XIAP. 8 XAF1 is widely expressed in most normal tissues, but in cancer tissues, its expression is very low or undetectable. [9][10][11] Recently, it was demonstrated that CpG dinucleotides upstream of the XAF1 start codon were differentially methylated in human gastric and colonic tumors, 9,12,13 further implicating that XAF1 acts as a tumor-suppressor gene.…”

“…8,14 Recently, it was reported that XAF1 can cooperate with tumor necrosis factor a (TNFa) in the induction of apoptosis. 15 These studies suggest that combining XAF1 with other cell death triggers might make a preferable choice for gene therapy.…”