XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis

Jeong, Seong In; Kim, Jung Wook; Ko, Kwanyoung; Ryu, Byeol; Lee, Min Goo; Kim, Hyo Jong; Gil, Sung

doi:10.1038/s41419-018-0867-4

Cited by 60 publications

(52 citation statements)

References 42 publications

(71 reference statements)

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“…The alternative splice site in exon 5 results in a large deletion of exon 5 (Fig 7E), but in-frame translation of exon 6. Importantly, the C-terminal domain is thought to be essential for binding to XIAP (31), and short isoforms are thought to function as dominant negative (22, 23), suggesting that these strain differences may lead to functional changes in XAF1.…”

Section: Resultsmentioning

confidence: 99%

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Passenger mutations confound phenotypes of SARM1-deficient mice

Uccellini¹,

Bardina²,

Sánchez-Aparicio³

et al. 2019

Preprint

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AbstractThe Toll/IL-1R domain-containing adaptor protein SARM1 is expressed primarily in the brain, where it mediates axonal degeneration. Additional roles for SARM1 in a number of other processes including TLR-signaling, viral infection, chemokine expression, and expression of the proapoptotic protein XAF1 have also been described. Much of the supporting evidence for SARM1 function has been generated by comparing WT C57BL/6 (B6) mice to SARM1-deficient mice backcrossed to the B6 background. Here we show that the Sarm1 gene lies in a gene-rich region encompassing XAF1, and the MIP and MCP chemokine family loci among other genes. Because gene-targeting of SARM1-deficient strains was done with 129 ES cells and these genes are too close to segregate, they remain 129 in sequence. As this could account for phenotypes attributed to SARM1, we generated new knockout mouse strains on a pure B6 background using CRISPR. Experiments in these new strains confirmed the role of SARM1 in axonal degeneration and susceptibility to WNV infection, but not in susceptibility to VSV or LACV infection, or chemokine or Xaf1 expression. Notably, the Xaf1 gene shows sequence variation between B6 and 129, resulting in coding changes and novel splice variants. Given its known role in apoptosis, XAF1 variants may account for some phenotypes described in previously made SARM1-deficient strains. RNAseq in the new strains reveal changes in the mitochondrial electron transport chain and ribosomal proteins, suggesting possible downstream targets of SARM1. Re-evaluation of described phenotypes in these new strains will be critical for defining the function of SARM1.

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Section: Resultsmentioning

confidence: 99%

“…Full-length isoforms are frequently downregulated in human tumors, while truncated isoforms are upregulated. Importantly, short forms have been reported to have dominant negative effects (22, 23).…”

Section: Introductionmentioning

confidence: 99%

Passenger mutations confound phenotypes of SARM1-deficient mice

Uccellini¹,

Bardina²,

Sánchez-Aparicio³

et al. 2019

Preprint

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“…X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) is identified as a pro-apoptotic protein and an antagonist of XIAP, counteracting anti-caspase activity of XIAP (43). It was demonstrated that XAF1 may promote cell apoptosis through in a multi-mechanism environment (44)(45)(46)(47). Down-regulated or deleted of XAF1 was observed in many malignancies, which suggesting that low expression of XAF1 may promote malignant tumor progression by relieving tumor cell apoptosis inhibition (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression reveals specific predictive biomarkers for renal cell carcinoma

Zhang¹,

Xu²,

Yin³

et al. 2020

Preprint

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Background We aimed to identify methylation-driven genes (MDGs) and predict the prognosis of clear cell renal cell carcinoma (ccRCC) based on several cohorts with high-throughput data.Methods The transcriptome profiles, 450K methylated data and corresponding clinical information were extracted from the cancer genome atlas (TCGA) database. MethylMix package was used to screen aberrant methylation events. Next, the Cox regression models were applied via survival package. Functional analysis was mainly performed based on ConsensusPathDB database. Besides, “mimifi” R package were adopted to analyze methylated alterations from three Gene Expression Omnibus (GEO) datasets. The predictive efficiency of constructed MDGs signature was assessed and validated in TCGA-KIRC and ICGC-RCC cohort, respectively. Unsupervised clustering analysis was conducted via ConsensusClusterPlus package. Moreover, MDGs-nomogram for OS prediction was conducted via glm and survival packages. Results Totally, we collected We finally identified 761 samples from TCGA-KIRC, ICGC-RCC, GSE61441, GSE105260 and GSE105261. We combined the expression data and 450K methylated data to find 5 hub prognostic MDGs (TAGLN2, PDK2, HHLA2, HOXA2, XAF1). We used the TCGA-KIRC cohort as the training dataset to verify the superior predictive significance of the 5 MDGs signature (AUC = 0.713), and validated it in ICGC-RCC cohort with AUC = 0.769. Kaplan-Meier analysis suggested that patients with high MDGs levels suffered from worse suvival outcomes. Besides, we further conducted the unsupervised clustering analysis in the whole ccRCC patients and identified the sub-cluster with the worst prognosis, indicating the MDGs could be used as efficient molecular classifier for ccRCC. We also identified 32 prognostic risk loci associated with hub MDGs in KIRC. Superior predictive efficiency was found in the MDGs-nomogram [Area Under Curve (AUC) of 3-year: 0.842, AUC of 5-year: 0.862], compared with traditional independent feature such as TNM stage (AUC of 3-year: 0.759, AUC of 5-year: 0.717). The 5 MDGs signature were mainly associated with oxygen metabolism, glycometabolism, even the HIF-1 signaling pathway. Conclusions Collectively, this study indicated several hub-MDGs and explored the prognostic value in ccRCC, which would provide new insights on the exploration of epigenetic pathogenesis and therapeutic targets for ccRCC.

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“…It is well known that, XAF1 as a proapoptotic tumor suppressor is always inactivated in multiple human cancers. XAF1 was identi ed ubiquitously in all normal adult and fetal tissues but was present in very low levels in a variety of cancer cell lines [41][42][43][44][45]. Both IFN-α2 and IFN-β were found to induce XAF1 transcription.…”

Section: Discussionmentioning

confidence: 99%

XAF1 is identified as a novel hub gene and associated with the clinical characteristics of lupus nephritis

Zeng¹,

Xie²,

Sun³

et al. 2020

Preprint

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Background Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that is the most common cause of morbidity and mortality. At present, the definitive therapies towards LN remains to be elucidated, so illuminating the molecular mechanism behind the disease has become an urgent task for researchers. This study set out to screen the hub genes of LN. Methods The microarray expression profile dataset GSE32591 from the Gene Expression Omnibus (GEO) database with 15 normal and 32 LN samples was assessed in this study. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the LN-related differentially expressed genes (DEGs). The Nephroseq database was performed to identify correlation analysis between unexplored hub genes and clinical features of LN. Additionally, the expression of the candidate genes was detected in the kidney tissue by immunohistochemistry. Results The 14 genes (13 upregulated and 1 downregulated) ultimately screened out as candidate hub genes of the pathogenesis of LN. Moreover, Correlation analysis between the unexplored hub genes and clinical features of LN suggested that XAF1 may involve in the progression of LN. Finally, our data demonstrated that the expression level of XAF1 was upregulated in LN compared with IgA nephropathy (IgAN) and related to the WHO Lupus Nephritis Class and the quantitative 24 h proteinuria of LN patients. Conclusions The current study proposed XAF1 as a novel hub gene in LN which may perform as a brand-new biomarker or therapeutic target of LN in the future.

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XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis

Cited by 60 publications

References 42 publications

Passenger mutations confound phenotypes of SARM1-deficient mice

Passenger mutations confound phenotypes of SARM1-deficient mice

Comprehensive analysis of DNA methylation and gene expression reveals specific predictive biomarkers for renal cell carcinoma

XAF1 is identified as a novel hub gene and associated with the clinical characteristics of lupus nephritis

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