Regulation of c-met expression by transcription repressor Daxx

Morozov, Viacheslav M.; Massoll, Nicole A.; Vladimirova, Olga; Maul, Gerd G.; Ishov, Alexander M.

doi:10.1038/sj.onc.1210865

Cited by 38 publications

(39 citation statements)

References 34 publications

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“…The expression of Wnt3a was also decreased in a time-dependent manner. By contrast, no significant changes were observed in the expression of Met, the level of which was regulated by signaling pathways other than Wnt/β-catenin (18,19). These findings indicate that exogenous DKK-3 protein downregulates the Wnt/β-catenin-targeted molecules of TCF1 and c-Myc.…”

Section: Exogenous Dkk-3 Inhibits the Downstream Targets Ofmentioning

confidence: 41%

“…As TCF1 is a transcription factor for c-Myc expression (4,5,21), the downregulation of TCF1 likely induced the gradual decrease in c-Myc levels. The protein expression levels of Met were also examined; Met is regulated by transcription factors other than TCF1 (18,19). There were no significant changes recorded in Met expression following treatment with recombinant DKK-3 protein, suggesting that its regulation is independent of exogenous DKK-3-associated modifications of Wnt/β-catenin signaling.…”

Section: Discussionmentioning

confidence: 99%

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Exogenous DKK‑3/REIC inhibits Wnt/β‑catenin signaling and cell proliferation in human kidney cancer KPK1

Sadahira

Kinoshita

et al. 2017

Oncol Lett

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Abstract. The third member of the Dickkopf family (DKK-3), also known as reduced expression in immortalized cells (REIC), is a tumor suppressor present in a variety of tumor cells. Regarding the regulation of the Wnt/β-catenin signaling pathway, exogenous DKK-1 and DKK-2 are reported to inhibit Wnt signaling by binding the associated effectors. However, whether exogenous DKK-3 inhibits Wnt signaling remains unclear. A recombinant protein of human full-length DKK-3 was used to investigate the exogenous effects of the protein in vitro in KPK1 human renal cell carcinoma cells. It was demonstrated that the expression of phosphorylated (p-)β-catenin (inactive form as the transcriptional factor) was increased in KPK1 cells treated with the exogenous DKK-3 protein. The levels of non-p-β-catenin (activated form of β-catenin) were consistently decreased. It was revealed that the expression of transcription factor (TCF) 1 and c-Myc, the downstream transcription factors of the Wnt/β-catenin signaling pathway, was inhibited following treatment with DKK-3. A cancer cell viability assay confirmed the anti-proliferative effects of exogenous DKK-3 protein, which was consistent with a suppressed Wnt/β-catenin signaling cascade. In addition, as low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor of DKK-1 and DKK-2 and their interaction on the cell surface inhibits Wnt/β-catenin signaling, it was examined whether the exogenous DKK-3 protein affects LRP6-mediated Wnt/β-catenin signaling. The LRP6 gene was silenced and the effects of DKK-3 on the time course of the upregulation of p-β-catenin expression were subsequently analyzed. Notably, LRP6 depletion elevated the base level of p-β-catenin; however, there was no significant effect on its upregulation course or expression pattern. These findings indicate that exogenous DKK-3 upregulates p-β-catenin and inhibits Wnt/β-catenin signaling in an LRP6-independent manner. Therefore, exogenous DKK-3 protein may inhibit the proliferation of KPK1 cells via inactivating Wnt/β-catenin signaling.

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Section: Exogenous Dkk-3 Inhibits the Downstream Targets Ofmentioning

confidence: 41%

Section: Discussionmentioning

confidence: 99%

Exogenous DKK‑3/REIC inhibits Wnt/β‑catenin signaling and cell proliferation in human kidney cancer KPK1

Sadahira

Kinoshita

et al. 2017

Oncol Lett

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“…Daxx has previously been reported to bind to and/or transcriptionally repress cellular and viral promoters, including c-met, RelB target genes and CMV (Croxton et al, 2006;Morozov et al, 2008;Puto and Reed, 2008;Reeves et al, 2010;Zhang et al, 2010). It is not known whether ATRX is required for the Daxx-mediated repression of these genes, however, the Drosophila ATRX homolog was recently shown to repress the pannier gene through a promotermediated mechanism (Valadez-Graham et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Single cell analysis of Daxx and ATRX-dependent transcriptional repression

Newhart¹,

Rafalska-Metcalf²,

Yang³

et al. 2012

Journal of Cell Science

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SummaryHistone H3.3 is a constitutively expressed H3 variant implicated in the epigenetic inheritance of chromatin structures. Recently, the PML-nuclear body (PML-NB)/Nuclear Domain 10 (ND10) proteins, Daxx and ATRX, were found to regulate replication-independent histone H3.3 chromatin assembly at telomeres and pericentric heterochromatin. As it is not completely understood how PML-NBs/ ND10s regulate transcription and resistance to viral infection, we have used a CMV-promoter-regulated inducible transgene array, at which Daxx and ATRX are enriched, to delineate the mechanisms through which they regulate transcription. When integrated into HeLa cells, which express both Daxx and ATRX, the array is refractory to activation. However, transcription can be induced when ICP0, the HSV-1 E3 ubiquitin ligase required to reverse latency, is expressed. As ATRX and Daxx are depleted from the activated array in ICP0-expressing HeLa cells, this suggests that they are required to maintain a repressed chromatin environment. As histone H3.3 is strongly recruited to the ICP0-activated array but does not co-localize with the DNA, this also suggests that chromatin assembly is blocked during activation. The conclusion that the Daxx and ATRX pathway is required for transcriptional repression and chromatin assembly at this site is further supported by the finding that an array integrated into the ATRX-negative U2OS cell line can be robustly activated and that histone H3.3 is similarly recruited and unincorporated into the chromatin. Therefore, this study has important implications for understanding gene silencing, viral latency and PML-NB/ND10 function.

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“…Daxx was first discovered as a cytoplasmic Fas death domain-associated protein (26). However, Daxx localization in promyelocytic nuclear bodies (PML-NBs) (27,28) and its association with numerous nuclear binding partners, including DNA-binding transcription factors and repressive epigenetic regulators (29)(30)(31)(32) and viral proteins (17,33,34), have suggested additional roles for Daxx (35).…”

mentioning

confidence: 99%

Retroviral DNA Methylation and Epigenetic Repression Are Mediated by the Antiviral Host Protein Daxx

Shalginskikh

Poleshko

Skalka

et al. 2013

J Virol

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Integrated retroviral DNA is subject to epigenetic transcriptional silencing at different frequencies. This process is mediated by repressive DNA methylation and histone modifications on viral chromatin. However, the detailed mechanisms by which retroviral silencing is initiated and maintained are not well understood. Using a model system in which avian sarcoma virus (ASV) DNA is epigenetically repressed in mammalian cells, we previously found that a cellular scaffolding protein, Daxx, acts as an antiretroviral factor that promotes epigenetic repression through recruitment of histone deacetylases (HDACs). Here we show that human Daxx protein levels are increased in response to retroviral infection and that Daxx acts at the time of infection to initiate epigenetic repression. Consistent with a rapid and active antiviral epigenetic response, we found that repressive histone marks and long terminal repeat (LTR) DNA methylation could be detected within 12 h to 3 days postinfection, respectively. Daxx was also found to be required for long-term ASV silencing maintenance and full viral DNA methylation, and it was physically associated with both viral DNA and DNA methyltransferases (DNMTs). These findings support a model in which incoming retroviral protein-DNA complexes are detected by Daxx, and the integrated provirus is rapidly chromatinized and repressed by DNA methylation and histone modification as part of an antiviral response. These results uncover a possible direct and active antiviral mechanism by which DNMTs can be recruited to retroviral DNA. Retroviruses are important agents of disease and serve as valuable vectors for gene delivery, and their study has provided seminal insights into cellular functions. A defining feature of retroviral replication is the integration of a DNA copy of the retroviral RNA genome into host chromatin, a process that establishes the DNA provirus. Integration provides a permanent association of viral DNA with the host cell and all of its progeny, and it also allows the provirus to efficiently mobilize the cellular transcriptional machinery for synthesis of viral mRNAs and viral RNA genomes.DNA integration is an essential step in retroviral replication, and it is catalyzed by the virus-encoded integrase (IN) protein. However, establishment of the provirus does not guarantee its expression; transcriptional repression by epigenetic mechanisms (epigenetic silencing) is often observed in both natural and interspecies retroviral infections. Examples include the silencing of retroviruses in embryonic stem cells (1, 2), the progressive silencing of expression of genes transduced by retroviral vectors during long-term cell propagation (3), and HIV latency (4). Epigenetic mechanisms also repress the expression of endogenous retroviruses (5-9).Retroviral epigenetic silencing is mediated by the enzymatic placement, and subsequent reading, of DNA methylation marks (addition of a methyl group to position 5 of the cytosine pyrimidine [5MeCpG]) and repressive nucleosomal histone modifications. Th...

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Regulation of c-met expression by transcription repressor Daxx

Cited by 38 publications

References 34 publications

Exogenous DKK‑3/REIC inhibits Wnt/β‑catenin signaling and cell proliferation in human kidney cancer KPK1

Exogenous DKK‑3/REIC inhibits Wnt/β‑catenin signaling and cell proliferation in human kidney cancer KPK1

Single cell analysis of Daxx and ATRX-dependent transcriptional repression

Retroviral DNA Methylation and Epigenetic Repression Are Mediated by the Antiviral Host Protein Daxx

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