Aberrant expression of ETS1 and ETS2 proteins in cancer

Fry, Elizabeth A.; Inoue, Kazushi

doi:10.15761/crr.1000151

Cited by 35 publications

(29 citation statements)

References 176 publications

(231 reference statements)

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“…To clarify whether ETS activity is required to induce ngf mRNA expression, we first made use of pharmacological inhibitors. ETS signaling is usually activated via the MAPKK-ERK1/2 pathway [ 28 ]. We therefore incubated 1321N1 cells with 5 µg/mL erinacine C together with either 20 µM PD98059 (MAPKK inhibitor) or 10 nM U0126 (ERK1/2 inhibitor) for 48 h followed by total RNA isolation, cDNA preparation, and semiquantitative RT-PCR to determine the ratio of ngf mRNA levels compared to gapdh mRNA.…”

Section: Resultsmentioning

confidence: 99%

Erinacine C Activates Transcription from a Consensus ETS DNA Binding Site in Astrocytic Cells in Addition to NGF Induction

et al. 2020

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Medicinal mushrooms of the genus Hericium are known to produce secondary metabolites with homeostatic properties for the central nervous system. We and others have recently demonstrated that among these metabolites cyathane diterpenoids and in particular erinacine C possess potent neurotrophin inducing properties in astrocytic cells. Yet, the signaling events downstream of erinacine C induced neurotrophin acitivity in neural-like adrenal phaeochromocytoma cells (PC12) cells have remained elusive. Similar, signaling events activated by erinacine C in astrocytic cells are unknown. Using a combination of genetic and pharmacological inhibitors we show that erinacine C induced neurotrophic activity mediates PC12 cell differentiation via the TrkA receptor and likely its associated PLCγ-, PI3K-, and MAPK/ERK pathways. Furthermore, a small library of transcriptional activation reporters revealed that erinacine C induces transcriptional activation mediated by DNA consensus binding sites of selected conserved transcription factor families. Among these, transcription is activated from an ETS consensus in a concentration dependent manner. Interestingly, induced ETS-consensus transcription occurs in parallel and independent of neurotrophin induction. This finding helps to explain the many pleiotropic functions of cyathane diterpenoids. Moreover, our studies provide genetic access to cyathane diterpenoid functions in astrocytic cells and help to mechanistically understand the action of cyathanes in glial cells.

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Section: Resultsmentioning

confidence: 99%

Erinacine C Activates Transcription from a Consensus ETS DNA Binding Site in Astrocytic Cells in Addition to NGF Induction

et al. 2020

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“…1d; Supplemental Table 2) (Guerquin et al 2013;Guzman-lepe et al 2018). For the top five TFs, we observed large down-regulated regulons for E2F4 and ETS1 (mainly involved in cell cycle) (Hsu and Sage 2016;Fry and Inoue 2018) with suppressed activity over time, and large up-regulated regulons for HNF4α, C/EBP, and STAT1 (mainly involved in differentiation) with increased activation over time ( Fig. 1d; Supplemental Fig.…”

Section: Transcriptome Analysis Of 3d Spheroid Hepg2 Differentiationmentioning

confidence: 78%

High-throughput confocal imaging of differentiated 3D liver-like spheroid cellular stress response reporters for identification of drug-induced liver injury liability

et al. 2019

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Adaptive stress response pathways play a key role in the switch between adaptation and adversity, and are important in druginduced liver injury. Previously, we have established an HepG2 fluorescent protein reporter platform to monitor adaptive stress response activation following drug treatment. HepG2 cells are often used in high-throughput primary toxicity screening, but metabolizing capacity in these cells is low and repeated dose toxicity testing inherently difficult. Here, we applied our bacterial artificial chromosome-based GFP reporter cell lines representing Nrf2 activation (Srxn1-GFP and NQO1-GFP), unfolded protein response (BiP-GFP and Chop-GFP), and DNA damage response (p21-GFP and Btg2-GFP) as long-term differentiated 3D liver-like spheroid cultures. All HepG2 GFP reporter lines differentiated into 3D spheroids similar to wild-type HepG2 cells. We systematically optimized the automated imaging and quantification of GFP reporter activity in individual spheroids using high-throughput confocal microscopy with a reference set of DILI compounds that activate these three stress response pathways at the transcriptional level in primary human hepatocytes. A panel of 33 compounds with established DILI liability was further tested in these six 3D GFP reporters in single 48 h treatment or 6 day daily repeated treatment. Strongest stress response activation was observed after 6-day repeated treatment, with the BiP and Srxn1-GFP reporters being most responsive and identified particular severe-DILI-onset compounds. Compounds that showed no GFP reporter activation in two-dimensional (2D) monolayer demonstrated GFP reporter stress response activation in 3D spheroids. Our data indicate that the application of BAC-GFP HepG2 cellular stress reporters in differentiated 3D spheroids is a promising strategy for mechanism-based identification of compounds with liability for DILI.

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“…Although AACTTT/AAAGTT is not labeled as a binding motif for a known transcription factor (TF), IRF1 is listed as the binding TF for this motif in (Xie et al, 2005). Among other binding partners, mir21 (Feng and Tsao, 2016; Javanmardi et al, 2017), mir204 (Li et al, 2016), mir211 Mazar et al, (2016), FOXO4 (Liu et al, 2011; Hornsveld et al, 2018), LEF1 (Hovanes et al, 2001; Li et al, 2009), ETS2 (Sizemore et al, 2017; Fry and Inoue, 2018) are all discussed in the context of a cancer.…”

Section: Resultsmentioning

confidence: 99%

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

Misra

Shih

Yan

et al. 2019

Preprint

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Craniosynostosis (CRS) is a congenital abnormality deformity with a heterogenous genetic contribution. Previously, there are two attempts to collect genes that are genetically associated with craniosynostosis and some related syndromes with 57 (Twigg and Wilkie, 2015) and 39 (Goos and Mathijssen, 2019) genes identified, respectively. We expanded this list of craniosynostosis genes by adding another 17 genes with an updated literature search. These genes are shown to be more likely to be intolerant to functional mutations. Of these 113 craniosynostosis genes, 21 (19% vs. 1.5% baseline frequency) are cancer driver genes, a 14-fold enrichment. The cancer-craniosynostosis connection is further validated by an over-representation analysis of craniosynostosis genes in KEGG cancer pathway and several cancer related gene-sets. Many cancer-craniosynostosis overlapping genes participate in intracellular signaling pathways, which play a role in both development and cancer. This connection can be viewed from the oncogenesis recapitulates ontogenesis framework. Nineteen craniosynostosis genes are transcription factor genes (16.8% vs. 8.2% baseline), and craniosynostosis genes are also enriched in targets of certain transcription factors or micro RNAs.

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Aberrant expression of ETS1 and ETS2 proteins in cancer

Cited by 35 publications

References 176 publications

Erinacine C Activates Transcription from a Consensus ETS DNA Binding Site in Astrocytic Cells in Addition to NGF Induction

Erinacine C Activates Transcription from a Consensus ETS DNA Binding Site in Astrocytic Cells in Addition to NGF Induction

High-throughput confocal imaging of differentiated 3D liver-like spheroid cellular stress response reporters for identification of drug-induced liver injury liability

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

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