A ubiquitin-like protein which is synergistically inducible by interferon-γ and tumor necrosis factor-α

Raasi, Shahri; Schmidtke, Gunter; Giuli, Rita de; Groettrup, Marcus

doi:10.1002/(sici)1521-4141(199912)29:12<4030::aid-immu4030>3.0.co;2-y

Cited by 111 publications

(103 citation statements)

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“…MZF-1) responsiveness. The existence of these responsive sites is consistent with the observations that the expression of FAT10 can be induced by IFN-g, TNF-a and/or retinoids (Raasi et al, 1999;Dokmanovic et al, 2002).…”

Section: Resultssupporting

confidence: 89%

“…FAT10 gene is localized to the telomeric end of the cluster of human major histocompatibility complex (MHC) class I (Fan et al, 1996) genes. In addition, it is expressed in dendritic cells and mature B cells (Bates et al, 1997) and can be synergistically induced by the IFNg and TNF-a cytokines (Raasi et al, 1999). Although the FAT10 gene resides at the telomeric end of the MHC class I genes, it was reported not to be a member of this class of genes Kumanovics et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers

2006

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FAT10 is a member of the ubiquitin-like modifier family of proteins and has been implicated to play important roles in antigen presentation, cytokine response, apoptosis and mitosis. We have recently demonstrated the upregulation of FAT10 gene expression in 90% of hepatocellular carcinoma patients. Here, we identified and characterized the promoter of the FAT10 gene to elucidate the mechanism of FAT10 gene expression. Notably, we found that the 5 0 untranslated region (5 0 UTR), from the transcription start site to 15 bases before the translational start site, displays significant promoter activity. Regions upstream of the 5 0 UTR (from þ 26 to À1997) do not confer any promoter activity. Curiously, FAT10 promoter activity and expression is significantly repressed in KB3-1 and HepG2 cells, which have wild-type p53, than in p53-negative Hep3B cells. The role of p53 in regulating FAT10 expression was evident by the significant downregulation (Po0.05) of FAT10 mRNA expression and promoter activity when wild-type p53 was transfected into p53-null Hep3B cells. Conversely, inhibiting p53 expression through siRNA against p53 significantly enhanced FAT10 expression and promoter activity. p53 was found to bind in vivo to the 5 0 half consensus sequence of p53-binding site located at the FAT10 promoter. Hence, we propose that FAT10 is a downstream target of p53 and dysregulation of FAT10 expression in p53-defective cells could contribute to carcinogenesis.

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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers

2006

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“…On the one hand FAT10 may act as a regulator of NF-B signaling and on the other hand FAT10 expression itself is regulated by NF-B. As already pointed out, FAT10 mRNA and protein expression is highly and synergistically inducible in all cell types by the pro-inflammatory cytokines IFN-␥ and TNF-␣ (Aichem et al, 2010;Raasi et al, 1999;Ren et al, 2011) or by a combination of TNF-␣ and IL-6 as shown in HepG2 cells (Choi et al, 2014). In HCT116 cells it was shown, that TNF-␣ signaling via the TNF-␣ receptor 1 (TNFR1) induced FAT10 expression, a receptor mainly found on tumor and stromal cells where it mediates the activation of NF-B (Balkwill, 2009;Ren et al, 2011).…”

Section: What Are the Mechanisms Behind Fat10 Overexpression?mentioning

confidence: 95%

“…Ebstein and colleagues (Ebstein et al, 2012) showed that FAT10 could enhance the MHC class I presentation of the human cytomegalovirus (HCMV)-derived antigen pp65 in HeLa cells by about two-fold as compared to untagged pp65 and Schliehe and colleagues (Schliehe et al, 2012) showed that the degradation rate as well as the presentation of specific lymphocyte choriomeningitis virus (LCMV) epitopes on MHC class I molecules was enhanced when FAT10 was fused to the N-terminus of the LCMV nucleoprotein. Apart from its expression in mTECs FAT10 is also constitutively expressed in mature B cells and dendritic cells (Bates et al, 1997) and its expression is highly and synergistically inducible on mRNA and protein level in numerous tissues and cell types by the pro-inflammatory cytokines IFN␥ and TNF␣ (Aichem et al, 2010;Raasi et al, 1999). A recent publication showed, that a high induction of FAT10 expression is also achieved by a synergistic treatment of HepG2 cells with TNF-␣ in combination with IL-6 (Choi et al, 2014).…”

Section: Fat10 In Adaptive and Innate Immunitymentioning

confidence: 99%

“…Of all these ULMs, FAT10 is the only modifier which acts as an autonomous transferable signal for degradation by the 26S proteasome and it was shown that this process can occur independently of ubiquitin (Hipp et al, 2005;Schmidtke et al, 2009). FAT10 is a protein of the immune system and it is strongly up-regulated by pro-inflammatory cytokines (Fan et al, 1996;Raasi et al, 1999) and during the maturation of antigen presenting cells (Buerger et al, 2015;Ebstein et al, 2009;Lukasiak et al, 2008). Moreover, numerous recent publications point to a direct involvement of FAT10 in cancer development.…”

Section: Introductionmentioning

confidence: 99%

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The ubiquitin-like modifier FAT10 in cancer development

Aichem

Groettrup

2016

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tDuring the last years it has emerged that the ubiquitin-like modifier FAT10 is directly involved in cancer development. FAT10 expression is highly up-regulated by pro-inflammatory cytokines IFN-␥ and TNF-␣ in all cell types and tissues and it was also found to be up-regulated in many cancer types such as glioma, colorectal, liver or gastric cancer. While pro-inflammatory cytokines within the tumor microenvironment probably contribute to FAT10 overexpression, an increasing body of evidence argues that pro-malignant capacities of FAT10 itself largely underlie its broad and intense overexpression in tumor tissues. FAT10 thereby regulates pathways involved in cancer development such as the NF-B-or Wnt-signaling. Moreover, FAT10 directly interacts with and influences downstream targets such as MAD2, p53 or ␤-catenin, leading to enhanced survival, proliferation, invasion and metastasis formation of cancer cells but also of non-malignant cells. In this review we will provide an overview of the regulation of FAT10 expression as well as its function in carcinogenesis.

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Interleukin‐32 Contributes to Human Nonalcoholic Fatty Liver Disease and Insulin Resistance

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder due to increased accumulation of fat in the liver and in many cases to enhanced inflammation. Although the contribution of inflammation in the pathogenesis of NAFLD is well established, the cytokines that are involved and how they influence liver transformation are still poorly characterized. In addition, with other modifiers, inflammation influences NAFLD progression to liver cirrhosis and hepatocellular carcinoma, demonstrating the need to find new molecular targets with potential future therapeutic applications. We investigated gene signatures in 38 liver biopsies from patients with NAFLD and obesity who had received bariatric surgery and compared these to 10 control patients who had received a cholecystectomy, using DNA microarray technology. A subset of differentially expressed genes was then validated on a larger cohort of 103 patients who had received bariatric surgery for obesity; data were thoroughly analyzed in terms of correlations with NAFLD pathophysiological parameters. Finally, the impact of a specific cytokine, interleukin‐32 (IL32), was addressed on primary human hepatocytes (PHHs). Transcript analysis revealed an up‐regulation of proinflammatory cytokines IL32, chemokine (C‐X‐C motif) ligand 9 (CXCL9), and CXCL10 and of ubiquitin D (UBD), whereas down‐regulation of insulin‐like growth factor‐binding protein 2 (IGFBP2) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) was reported in patients with NAFLD. Moreover, IL32, which is the major deregulated gene, correlated with body mass index (BMI), waist circumference, NAFLD activity score (NAS), aminotransferases (alanine aminotransferase [ALAT] and aspartate aminotransferase [ASAT]), and homeostasis model assessment of insulin resistance (HOMA‐IR) index in patients. Consistent with an instrumental role in the pathophysiology of NAFLD, treatment of control human hepatocytes with recombinant IL32 leads to insulin resistance, a hallmark metabolic deregulation in NAFLD hepatocytes. Conclusion: IL32 has a critical role in the pathogenesis of NAFLD and could be considered as a therapeutic target in patients.

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A ubiquitin-like protein which is synergistically inducible by interferon-γ and tumor necrosis factor-α

Cited by 111 publications

References 13 publications

p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers

p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers

The ubiquitin-like modifier FAT10 in cancer development

Interleukin‐32 Contributes to Human Nonalcoholic Fatty Liver Disease and Insulin Resistance

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