FAT 10, a gene up-regulated in various cancers, is cell-cycle regulated

Lim, Chuan-Bian; Zhang, Dongwei; Lee, Caroline

doi:10.1186/1747-1028-1-20

Cited by 48 publications

(31 citation statements)

References 23 publications

(33 reference statements)

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“…The observation that FAT10 modifies p53 and stimulates its transcriptional activity is in agreement with the potential roles of FAT10 in the regulation of cell-cycle, apoptosis, proliferation arrest, and tumorigenesis [5, 7, 8]. The consequence of p53 stimulation is defined by ‘cellular context’ or particular cell genotype [26].…”

Section: Discussionsupporting

confidence: 61%

“…FAT10 is originally identified as a gene encoded in the major histocompatibility complex class I locus and is inducible with TNF-α and interferon-γ [4]. It is regulated in a cell-cycle dependent fashion with the highest expression at the S phase [5], and is negatively regulated by p53 [6]. Although the functions of FAT10 are unclear, it has been implicated to play important roles in many cellular processes.…”

Section: Introductionmentioning

confidence: 99%

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FAT10 modifies p53 and upregulates its transcriptional activity

Santockyte

et al. 2011

Archives of Biochemistry and Biophysics

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FAT10, also known as diubiquitin, has been implicated in the regulation of diverse cellular processes, including mitosis, immune response, and apoptosis. We seek to identify FAT10-targeted proteins, an essential step in elucidating the physiological function of FAT10. To this end, human FAT10 or its non-conjugatable derivative, FAT10ΔGG, was overexpressed in HEK293 cells. We observed a number of high molecular weight FAT10 conjugates in cells expressing wild-type FAT10, but not in FAT10ΔGG. The FAT10 conjugates are inducible by TNF-α and accumulated significantly when cells were treated with proteasome inhibitor, MG132. Among them, tumor suppressor p53 was found to be FATylated. The p53 transcriptional activity was found to be substantially enhanced in FAT10-overexpressing cells. In addition, overexpressing FAT10 in HEK293 cells also reduced the population of p53 which cross reacted with monoclonal anti-p53 antibody, PAB240, known to recognize only the transcriptionally inactive p53. FAT10 in the nucleus was found co-localized with p53 and altered its subcellular compartmentalization. Furthermore, overexpressing FAT10 led to a reduction in the size of promyelocytic leukemia nuclear bodies (PML-NBs) and altered their distribution in the nucleus. Based on these observations, a potential mechanism which correlates FATylation of p53 to its translocation and transcriptional activation is discussed.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

FAT10 modifies p53 and upregulates its transcriptional activity

Santockyte

et al. 2011

Archives of Biochemistry and Biophysics

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“…FAT10 is overexpressed in numerous types of malignancies, including HCC, colorectal tumors, gastric tumors and gynecological tumors ( 8 , 9 , 29 ). Previous studies have suggested that FAT10 has a pathological role in cancer via involvement in mechanisms other than its proteasome targeting function ( 29 ). However, the role of FAT10 in tumorigenesis remains undetermined.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin‑like protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen

Chen¹,

Zhang²,

Yun³

et al. 2018

Mol Med Report

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In response to DNA damage, proliferating cell nuclear antigen (PCNA) has an important role as a positive regulator and as a scaffold protein associated with DNA damage bypass and repair pathways by serving as a platform for the recruitment of associated components. As demonstrated in the present study, the ubiquitin-like modifier human leukocyte antigen F locus adjacent transcript 10 (FAT10), which binds to PCNA but has not previously been demonstrated to be associated with the DNA damage response (DDR), is induced by ultraviolet/ionizing radiation and VP-16 treatment in HeLa cells. Furthermore, DNA damage enhances FAT10 expression. Immunoprecipitation analysis suggested PCNA is modified by FAT10, and the degradation of FATylated PCNA located in the cytoplasm is regulated by the 26S proteasome, which is also responsible for the upregulation of nuclear foci formation. Furthermore, immunofluorescence experiment suggested FAT10 co-localizes with PCNA in nuclear foci, thus suggesting that FATylation of PCNA may affect DDR via the induction of PCNA degradation in the cytoplasm or nucleus. In addition, immunohistochemistry experiment suggested the expression levels of FAT10 and PCNA are enhanced in HCC tissues compared with healthy liver tissues; however, the expression of FAT10 is suppressed in regenerated liver tissues, which express high levels of PCNA, thus suggesting that the association between FAT10 and PCNA expression is only exhibited in tumor tissues. In conclusion, the results of the present study suggest that FAT10 may be involved in DDR and therefore the progression of tumorigenesis.

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“…FAT10 expression is induced by interferon (IFN)-γ and tumor necrosis factor α (TNFα) (Lukasiak et al , 2008; Oliva et al , 2010). Increased FAT10 gene expression and protein levels have been observed in various cancers (Raasi et al , 2001; Lee et al , 2003; Lim et al , 2006; Qing et al , 2011), and interference of FAT10 could suppress cell proliferation by inhibiting the cell cycle S-phase entry and inducing apoptosis (Chen et al , 2014). Despite these reports, the biological significance of the FAT10 system in liver tumor development remains unclear and warrants further research.…”

Section: Introductionmentioning

confidence: 99%

Ufmylation and FATylation pathways are downregulated in human alcoholic and nonalcoholic steatohepatitis, and mice fed DDC, where Mallory–Denk bodies (MDBs) form

Liu

Tillman

et al. 2014

Experimental and Molecular Pathology

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We previously reported the mechanisms involved in the formation of Mallory-Denk bodies (MDBs) in mice fed DDC. To further provide clinical evidence as to how ubiquitin-like protein (Ubls) modification, gene transcript expression in Ufmylation and FATylation were investigated in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies and frozen liver sections from DDC re-fed mice were used. Real-time PCR analysis showed that all Ufmylation molecules (Ufm1, Uba5, Ufc1, Ufl1 and UfSPs) were significantly down regulated, both in DDC re-fed mice livers and patients’ livers where MDBs had formed, indicating that gene transcript changes were limited to MDB-forming livers where the protein quality control system was down regulated. FAT10 and subunits of the immunoproteasome (LMP2 and LMP7) were both up regulated as previously shown. An approximate 176- and 5-fold up regulation (respectively) of FAT10 were observed in the DDC re-fed mice liver and in the livers of human alcoholic hepatitis with MDBs present, implying that there was an important role played by this gene. The FAT10-specific E1 and E2 enzymes Uba6 and USE1, however, were found to be down regulated both in patients’ livers and in the liver of DDC re-fed mice. Interestedly, the down regulation of mRNA levels was proportionate to MDB abundance in the liver tissues. Our results show the first systematic demonstration of transcript regulation of Ufmylation and FATylation in the liver of patients who form MDBs, where protein quality control is down regulated. This was also shown in livers of DDC re-fed mice where MDBs had formed.

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FAT 10, a gene up-regulated in various cancers, is cell-cycle regulated

Cited by 48 publications

References 23 publications

FAT10 modifies p53 and upregulates its transcriptional activity

FAT10 modifies p53 and upregulates its transcriptional activity

Ubiquitin‑like protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen

Ufmylation and FATylation pathways are downregulated in human alcoholic and nonalcoholic steatohepatitis, and mice fed DDC, where Mallory–Denk bodies (MDBs) form

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