NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor

Mori, T.; Ikeda, Daisuke; Fukushima, Toshihiko; Takenoshita, Seiichi; Kochi, Hideo

doi:10.4161/cc.10.19.17176

Cited by 41 publications

(77 citation statements)

References 85 publications

(137 reference statements)

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“…However, the results of our study indicate a different role for UHRF2 in the deregulated cell cycle of glioma cells. The protein-protein interaction network shows that UHRF2 forms complexes with cyclins (A, B, D, and E), cyclin-dependent kinases (CDK1,CDK2, CDK4, and CDK6), proliferating cell nuclear antigen (PCNA), p53, pRB, chromatin proteins, chromatin modifiers (HDAC1 and DNMTs), and hepatitis B virus core protein (Mori et al, 2011;Qian et al, 2012). The actual mechanism may be hidden under this complex interaction network.…”

Section: Discussionmentioning

confidence: 99%

“…UHRF2 has been reported to be a ubiquitin ligase that interacts with the CDK2-cyclin E complex and induces G1 arrest of the HEK293 human embryonic kidney cell line Mori et al, 2004). Studies on UHRF2 have demonstrated that it constitutes a nodal point in the cell cycle network (Mori et al, 2011). Because this protein possesses a ubiquitin-like (UBL) domain, tandem Tudor domain (TTD), plant homeo domain (PHD) finger domain, SET and RING-associated (SRA) domain, and new gene (RING) finger domain at the C-terminus, its functions are more complex than an ordinary cell cycle hub protein (Glaab et al, 2010;Mori et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

Zhang²,

Su³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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UHRF2 is a member of the ubiquitin plant homeo domain RING finger family, which has been proven to be frequently up-regulated in colorectal cancer cells and play a role as an oncogene in breast cancer cells. However, the role of UHRF2 in glioma cells remains unclear. In this study, we performed real-time quantitative PCR on 32 pathologically confirmed glioma samples (grade I, 4 cases; grade II, 11 cases; grade III, 10 cases; and grade IV, 7 cases; according to the 2007 WHO classification system) and four glioma cell lines (A172, U251, U373, and U87). The expression of UHRF2 mRNA was significantly lower in the grade III and grade IV groups compared with the noncancerous brain tissue group, whereas its expression was high in A172, U251, and U373 glioma cell lines. An in vitro assay was performed to investigate the functions of UHRF2. Using a lentivirus-based RNA interference (RNAi) approach, we down-regulated UHRF2 expression in the U251 glioma cell line. This downregulation led to the inhibition of cell proliferation, an increase in cell apoptosis, and a change of cell cycle distribution, in which S stage cells decreased and G2/M stage cells increased. Our results suggest that UHRF2 may be closely related to tumorigenesis and the development of gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

Zhang²,

Su³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…To determine how NVP-BEZ235 induces G 1 arrest in GSCs, we examined the expression of endogenous cyclins in SU-2 cells after 48 h of treatment with IR (8 Gy) and NVP-BEZ235 (10 nmol/L). Cyclin A is involved in meiotic progression and has markedly lower expression in cells arrested in the G 1 phase [33][34][35] . Cyclin D1 is a key regulator of the G 1 to S phase progression and is aberrantly expressed in numerous human cancers [36] .…”

Section: G 1 Phase Block Induced By Ir and Nvp-bez235mentioning

confidence: 99%

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

et al. 2013

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Aim: NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor and shows dramatic effects on gliomas. The aim of this study was to investigate the effects of NVP-BEZ235 on the radiosensitivity and autophagy of glioma stem cells (GSCs) in vitro. Methods: Human GSCs (SU-2) were tested. The cell viability and survival from ionizing radiation (IR) were evaluated using MTT and clonogenic survival assay, respectively. Immunofluorescence assays were used to identify the formation of autophagosomes. The apoptotic cells were quantified with annexin V-FITC/PI staining and flow cytometry, and observed using Hoechst 33258 staining and fluorescence microscope. Western blot analysis was used to analyze the expression levels of proteins. Cell cycle status was determined by measuring DNA content after staining with PI. DNA repair in the cells was assessed using a comet assay. Results: Treatment of SU-2 cells with NVP-BEZ235 (10-320 nmol/L) alone suppressed the cell growth in a concentration-dependent manner. A low concentration of NVP-BEZ235 (10 nmol/L) significantly increased the radiation sensitivity of SU-2 cells, which could be blocked by co-treatment with 3-MA (50 µmol/L). In NVP-BEZ235-treated SU-2 cells, more punctate patterns of microtubule-associated protein LC3 immunoreactivity was observed, and the level of membrane-bound LC3-II was significantly increased. A combination of IR with NVP-BEZ235 significantly increased the apoptosis of SU-2 cells, as shown in the increased levels of BID, Bax, and active caspase-3, and decreased level of Bcl-2. Furthermore, the combination of IR with NVP-BEZ235 led to G 1 cell cycle arrest. Moreover, NVP-BEZ235 significantly attenuated the repair of IR-induced DNA damage as reflected by the tail length of the comet. Conclusion: NVP-BEZ235 increases the radiosensitivity of GSCs in vitro by activating autophagy that is associated with synergistic increase of apoptosis and cell-cycle arrest and decrease of DNA repair capacity.

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“…Like UHRF1, UHRF2 was also implicated in tumors; but reports about the role of UHRF2 in tumors are contradictory and uncertain. Some studies demonstrated that UHRF2 behaves like a tumor suppressor to inhibit the inappropriate cell cycle progression (31,32), whereas other studies suggested potential oncogenic characteristics of UHRF2 with up-regulated expression in cancers (37)(38)(39)(40).…”

Section: Uhrf2 Is a Transcription Co-regulator Formentioning

confidence: 99%

“…A function of UHRF2 in regulation of cell cycle was also speculated. UHRF2 was found to interact with cyclins, CDKs, p53, pRB, PCNA, and was able to induce G1 arrest by ubiquitinating cyclins D1 and E1 (31,32). Other substrates of UHRF2 E3 Ub ligase include PCNP, nuclear aggregates containing polyglutamine repeats, hepatitis B virus core protein and zinc finger protein 131 (ZNF131) (33)(34)(35)(36).…”

Section: Uhrf2 Is a Transcription Co-regulator Formentioning

confidence: 99%

Multidimensional Proteomics Reveals a Role of UHRF2 in the Regulation of Epithelial-Mesenchymal Transition (EMT)

Lai

Liang

Chen

et al. 2016

Molecular & Cellular Proteomics

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UHRF1 is best known for its positive role in the maintenance of DNMT1-mediated DNA methylation and is implicated in a variety of tumor processes. In this paper, we provided evidence to demonstrate a role of UHRF2 in cell motility and invasion through the regulation of the epithelial-mesenchymal transition (EMT) process by acting as a transcriptional co-regulator of the EMT-transcription factors (TFs). We ectopically expressed UHRF2 in gastric cancer cell lines and performed multidimensional proteomics analyses. Proteome profiling analysis suggested a role of UHRF2 in repression of cell-cell adhesion; analysis of proteome-wide TF DNA binding activities revealed the up-regulation of many EMT-TFs in UHRF2-overexpressing cells. These data suggest that UHRF2 is a regulator of cell motility and the EMT program. Indeed, cell invasion experiments demonstrated that silencing of UHRF2 in aggressive cells impaired their abilities of migration and invasion in vitro. Further ChIP-seq identified UHRF2 genomic binding motifs that coincide with several TF binding motifs including EMT-TFs, and the binding of UHRF2 to CDH1 promoter was validated by ChIP-qPCR. Moreover, the interactome analysis with IP-MS uncovered the interaction of UHRF2 with TFs including TCF7L2 and several protein complexes that regulate chromatin remodeling and histone modifications, suggesting that UHRF2 is a transcription co-regulator for TFs such as TCF7L2 to regulate the EMT process. Taken together, our study identified a role of UHRF2 in EMT and tumor metastasis and demonstrated an effective approach to obtain clues of UHRF2 function without prior knowledge through combining evidence from multidimensional proteomics analyses. Molecular & Cellular

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NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor

Cited by 41 publications

References 85 publications

UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

UHRF2 mRNA Expression is Low in Malignant Glioma but Silencing Inhibits the Growth of U251 Glioma Cells in vitro

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

Multidimensional Proteomics Reveals a Role of UHRF2 in the Regulation of Epithelial-Mesenchymal Transition (EMT)

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