RNF135, RING finger protein, promotes the proliferation of human glioblastoma cells in vivo and in vitro via the ERK pathway

Liu, Yongjian; Wang, Feng; Liu, Yongsheng; Yao, Yu; Lv, Xiupeng; Dong, Bin; Li, Jun; Ren, Siyang; Yao, Yiwen; Xu, Yunhua

doi:10.1038/srep20642

Cited by 35 publications

(31 citation statements)

References 45 publications

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“…The RNF135 gene has been shown to be down-regulated in cells from malignant peripheral nerve sheath tumours (MPNSTs) and MPNST cell lines suggesting that RNF135 loss is involved in conferring the increased MPNST risk characteristic of NF1 microdeletion patients (Pasmant et al 2011). In glioblastomas, however, RNF135 has been found to be upregulated and promotes the proliferation of human glioblastoma cells in vivo and in vitro via the ERK pathway (Liu et al 2016). Furthermore, RNF135 would appear to promote the expression of PTEN and TP53 in tongue cancer SCC25 cells and RNF135 overexpression inhibits the viability, proliferation, and invasion of these cells (Jin et al 2016).…”

Section: Co-deleted Genes With the Potential To Influence The Clinicamentioning

confidence: 99%

Emerging genotype–phenotype relationships in patients with large NF1 deletions

2017

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The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16–26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8–13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype–phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

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Section: Co-deleted Genes With the Potential To Influence The Clinicamentioning

confidence: 99%

Emerging genotype–phenotype relationships in patients with large NF1 deletions

2017

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“…Thus, it is expected that Riplet targets the proteins involved in these conditions. There are several reports that Riplet and TRIM25 are involved in tumorigenesis ( 42 , 45 , 46 ). As several viruses have the ability to abrogate the described ubiquitin ligases, it is expected that viral protein-mediated inhibition of the ubiquitin ligases affects both innate immunity and other phenomena, such as virus-induced tumorigenesis and neuropsychiatric disorders.…”

Section: Perspectivesmentioning

confidence: 99%

Regulation of RIG-I Activation by K63-Linked Polyubiquitination

Okamoto¹,

Kouwaki²,

Fukushima³

et al. 2018

Front. Immunol.

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RIG-I is a pattern recognition receptor and recognizes cytoplasmic viral double-stranded RNA (dsRNA). Influenza A virus, hepatitis C virus, and several other pathogenic viruses are mainly recognized by RIG-I, resulting in the activation of the innate immune responses. The protein comprises N-terminal two caspase activation and recruitment domains (2CARDs), an RNA helicase domain, and the C-terminal domain (CTD). The CTD recognizes 5′-triphosphate viral dsRNA. After recognition of viral dsRNA, the protein harbors K63-linked polyubiquitination essential for RIG-I activation. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. MAVS aggregation then triggers the signal to induce the innate immune responses. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. MEX3C and TRIM4 mediate polyubiquitination of the 2CARDs. By contrast, Riplet ubiquitinates the CTD. The physiological significance of each ubiquitin ligases has been shown by knockout and knockdown studies, but there appears to be contradictory to evidence reported in the literature. In this review, we summarize recent findings related to K63-linked polyubiquitination and propose a model that could reconcile current contradictory theories. We also discuss the physiological significance of the ubiquitin ligases in the immune system against viral infection.

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“…E3 ubiquitin-protein is a peptide ligase that have been identified as a bio-marker and therapeutic target of glioblastoma ( 8 ). Ring finger protein 138 (RNF138) is a member of the E3 ligase family, which contains an N-terminal Cys(3)-His-Cys(4) ring finger protein domain, three zinc-finger-like domains and a C-terminal ubiquitin-interacting motif (UIM) type ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway

Feng

et al. 2018

Oncol Rep

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Glioma is the most common adult malignant primary brain tumor; however, the effect of chemotherapy is often limited by drug-resistance and poor prognosis is common. Ring finger protein 138 (RNF138) belongs to the E3 ligase family, and has significantly higher expression level in glioma tissue than in noncancerous brain tissues. Epithelial-mesenchymal-transition (EMT) has a critical role in cancer invasion and metastasis, ultimately leading to increased cell motility and resistance to genotoxic agents. Extracellular-signal regulated kinase (Erk) pathways promote the growth of glioma cells and enhance tumor invasion, with a role in the progression of EMT. However, the association between RNF138 and human glioma progression remains poorly understood. Relatively little is known about the association between RNF138, Erk, and EMT in glioma progression. In the current study, experiments were performed to explore the potential roles and mechanisms of RNF138 in glioblastoma in vitro and in vivo. Glioma cell line proliferation, migration and invasion were inhibited by knockdown of RNF138 in vitro. By lowering the RNF138 expression, cleaved caspase3 and E-cadherin were upregulated, while phospho-Erk1/2, vimentin, MMP2, HIF-1α and VEGF were downregulated in U87 and U251 cells in vitro. In vivo findings revealed that the growth of U87 cell-transplanted tumors in nude mice was inhibited in tumors with RNF138 knockdown. These findings suggested that downregulation of RNF138 inhibited glioma cell proliferation, migration, and invasion, and reversed EMT, potentially via Erk signaling pathway. Therefore, RNF138 may be a potential therapeutic target against glioma.

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RNF135, RING finger protein, promotes the proliferation of human glioblastoma cells in vivo and in vitro via the ERK pathway

Cited by 35 publications

References 45 publications

Emerging genotype–phenotype relationships in patients with large NF1 deletions

Emerging genotype–phenotype relationships in patients with large NF1 deletions

Regulation of RIG-I Activation by K63-Linked Polyubiquitination

Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway

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