Leaman DW, Chawla-Sarkar M, Vyas K, Reheman M, Tamai K, Toji S and Borden ECIdentification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis. J. Biol. Chem. 277: 28504-28511

Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2002; 277(32):28504-11. DOI: 10.1074/jbc.M204851200
Source: PubMed


In the course of gene array studies aimed at identifying IFN-stimulated genes associated with interferon beta (IFN-beta)-induced apoptosis, we identified X-linked inhibitor of apoptosis-associated factor-1 (XAF1) as a novel IFN-stimulated gene. XAF1 mRNA was up-regulated by IFN-alpha and IFN-beta in all cells examined. However, IFNs induced high levels of XAF1 protein predominantly in cell lines sensitive to the proapoptotic effects of IFN-beta. In apoptosis-resistant cells including WM164 melanoma, WM35 melanoma, U937 pro-monocytic leukemia, and HT1080 fibrosarcoma cells, XAF1 mRNA was strongly up-regulated but XAF1 protein was up-regulated only weakly or not at all. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a critical mediator of IFN-beta-induced apoptosis, but most melanoma cell lines were resistant to recombinant TRAIL protein. For example, A375 melanoma cells were defective in TRAIL induction by IFN-beta and were resistant to TRAIL-induced apoptosis. However, IFN-beta pretreatment sensitized them to subsequent recombinant TRAIL-induced apoptosis. A375 cells expressing XAF1 constitutively were more sensitive to TRAIL-induced apoptosis compared with empty vector-transfected cells. The degree of sensitization by XAF1 was similar to that provided by IFN pretreatment and was correlated with the level of XAF1 expressed. Furthermore, the overexpression of the zinc-finger portion of XAF1 blocked IFN-dependent sensitization of A375 melanoma cells to the proapoptotic effects of TRAIL. These results suggested that IFN-dependent induction of XAF1 strongly influenced cellular sensitivity to the proapoptotic actions of TRAIL.

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    • "XAF1 antagonizes XIAP activities, thereby promoting apoptosis [9]. XAF1 can dramatically sensitize cancer cells to apoptotic triggers such as TRAIL, etoposide treatments 5-fluorouracil [10], H2O2, c-irradiation, ultraviolet [11], and tumour necrosis factor-α, which are independent of its interaction with XIAP [12]. XAF1 is therefore believed to play an important role in the major apoptosis-related pathways. "
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    ABSTRACT: Somatostatin prevents cell proliferation by inducing apoptosis. Downregulation of the XAF1 transcript may occur during the development of prostate cancer. It is interesting to evaluate the potential regulatory effects of somatostatin on XAF1 expression during the development of prostate cancer cells. XAF1 mRNA and protein expression in human prostate epithelial cells RWPE-1, androgen dependent prostate cancer LNCaP, and androgen independent DU145 and PC3 cells were evaluated using RT-PCR and Western blot. The regulation of XAF1 mRNA and protein expression by somatostatin and its analogue Octreotide was evaluated. Substantial levels of XAF1 mRNA and proteins were detected in RWPE-1 cells, whereas prostate cancer cells LNCaP, DU145 and PC3 exhibited lower XAF1 expression. Somatostatin and Octreotide up-regulated XAF1 mRNA and protein expression in all prostate cancer cell lines. XAF1 down-regulation may contribute to the prostate cancer development. The enhanced XAF1 expression by somatostatin indicates a promising strategy for prostate cancer therapy.
    Journal of Experimental & Clinical Cancer Research 12/2010; 29(1):162. DOI:10.1186/1756-9966-29-162 · 4.43 Impact Factor
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    • "Similarly to CSFV, a study with the Ebola Virus, which also induces bystander killing lymphopenia, showed that a high proportion of cells expressed TRAIL rather than FAS and FASL suggesting that the TRAIL pathway could be preferentially involved during Ebola-induced lymphocyte cell death [9]. Lastly, X-linked inhibitor of apoptosis (XIAP) associated factor 1 (XAF1), shown by our results to be up-regulated during CSFV infection, is a crucial “cell death/apoptosis-related ISG” mediator of IFN-induced apoptosis via TRAIL [20, 28]. "
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    Veterinary Research 10/2009; 41(1):7. DOI:10.1051/vetres/2009055 · 2.82 Impact Factor
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    • "The pro-survival activity of XIAP can be reversed by IAP-antagonists such as the mitochondrial protein Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI) [15,16] and the nuclear protein XAF1 [17,18]. XAF1 has been identified as an interferon (IFN)-inducible tumour suppressor gene, which's expression sensitizes cancer cells to several apoptotic stimuli [18,19]. The pro-apoptotic effects of XAF1 may be mediated by direct sequestration of XIAP from the cytosol to the nucleus, thus antagonizing the inhibition of caspases [18]. "
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    ABSTRACT: Decreased expression of the interferon-stimulated, putative tumour suppressor gene XAF1 has been shown to play a role during the onset, progression and treatment failure in various malignancies. However, little is yet known about its potential implication in the tumour biology of clear-cell renal cell cancer (ccRCC). This study assessed the expression of XAF1 protein in tumour tissue obtained from 291 ccRCC patients and 68 normal renal tissue samples, utilizing immunohistochemistry on a tissue-micro-array. XAF1 expression was correlated to clinico-pathological tumour features and prognosis. Nuclear XAF1 expression was commonly detected in normal renal- (94.1%) and ccRCC (91.8%) samples, without significant differences of expression levels. Low XAF1 expression in ccRCC tissue, however, was associated with progression of tumour stage (p = 0.040) and grade (p < 0.001). Low XAF1 tumour levels were also prognostic of significantly shortened overall survival times in univariate analysis (p = 0.018), but did not provide independent prognostic information. These data suggest down-regulation of XAF1 expression to be implicated in ccRCC progression and implies that its re-induction may provide a therapeutic approach. Although the prognostic value of XAF1 in ccRCC appears to be limited, its predictive value remains to be determined, especially in patients with metastatic disease undergoing novel combination therapies of targeted agents with Interferon-alpha.
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