Pro-inflammatory cytokine and high doses of ionizing radiation have similar effects on the expression of NF-kappaB-dependent genes

Janus, Patryk; Szołtysek, Katarzyna; Zając, Gracjana; Stokowy, Tomasz; Walaszczyk, Anna; Widłak, Wiesława; Wojtaś, Bartosz; Gielniewski, Bartłomiej; Iwanaszko, Marta; Braun, Rosemary; Cockell, Simon; Perkins, Neil D.; Kimmel, Marek; Widłak, Piotr

doi:10.1016/j.cellsig.2018.02.011

Cited by 28 publications

(25 citation statements)

References 56 publications

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“…To further test the effects of perturbations targeting ceRNA regulators on the activity of their protein targets, we used VIPER to analyze 13 high-throughput assays where each of the six genes was targeted by RNAi and genome-wide expression was measured by microarrays or RNA-Seq ( 75–85 ). To determine whether VIPER could be used to evaluate these assays, we first tested whether silencing of each gene resulted in a significant ( P < 0.05, VIPER) dysregulation to its inferred activity; e.g.…”

Section: Resultsmentioning

confidence: 99%

The number of titrated microRNA species dictates ceRNA regulation

Chiu

Martínez

Komissarova

et al. 2018

Nucleic Acids Research

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AbstractmicroRNAs (miRNAs) play key roles in cancer, but their propensity to couple their targets as competing endogenous RNAs (ceRNAs) has only recently emerged. Multiple models have studied ceRNA regulation, but these models did not account for the effects of co-regulation by miRNAs with many targets. We modeled ceRNA and simulated its effects using established parameters for miRNA/mRNA interaction kinetics while accounting for co-regulation by multiple miRNAs with many targets. Our simulations suggested that co-regulation by many miRNA species is more likely to produce physiologically relevant context-independent couplings. To test this, we studied the overlap of inferred ceRNA networks from four tumor contexts—our proposed pan-cancer ceRNA interactome (PCI). PCI was composed of interactions between genes that were co-regulated by nearly three-times as many miRNAs as other inferred ceRNA interactions. Evidence from expression-profiling datasets suggested that PCI interactions are predictive of gene expression in 12 independent tumor- and non-tumor contexts. Biochemical assays confirmed ceRNA couplings for two PCI subnetworks, including oncogenes CCND1, HIF1A and HMGA2, and tumor suppressors PTEN, RB1 and TP53. Our results suggest that PCI is enriched for context-independent interactions that are coupled by many miRNA species and are more likely to be context independent.

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Section: Resultsmentioning

confidence: 99%

The number of titrated microRNA species dictates ceRNA regulation

Chiu

Martínez

Komissarova

et al. 2018

Nucleic Acids Research

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“…Human osteosarcoma U2-OS cells were selected as an experimental model where the activation of a classical p53-dependent pathway [ 44 ] and the NF-κB pathway [ 45 ] was observed in response to ionizing radiation. The wild-type U2-OS cells were purchased from the American Type Culture Collection (ATCC HTB-96) and used as a primary model.…”

Section: Methodsmentioning

confidence: 99%

RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation

et al. 2018

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BackgroundThe cellular response to ionizing radiation involves activation of p53-dependent pathways and activation of the atypical NF-κB pathway. The crosstalk between these two transcriptional networks include (co)regulation of common gene targets. Here we looked for novel genes potentially (co)regulated by p53 and NF-κB using integrative genomics screening in human osteosarcoma U2-OS cells irradiated with a high dose (4 and 10 Gy). Radiation-induced expression in cells with silenced TP53 or RELA (coding the p65 NF-κB subunit) genes was analyzed by RNA-Seq while radiation-enhanced binding of p53 and RelA in putative regulatory regions was analyzed by ChIP-Seq, then selected candidates were validated by qPCR.ResultsWe identified a subset of radiation-modulated genes whose expression was affected by silencing of both TP53 and RELA, and a subset of radiation-upregulated genes where radiation stimulated binding of both p53 and RelA. For three genes, namely IL4I1, SERPINE1, and CDKN1A, an antagonistic effect of the TP53 and RELA silencing was consistent with radiation-enhanced binding of both p53 and RelA. This suggested the possibility of a direct antagonistic (co)regulation by both factors: activation by NF-κB and inhibition by p53 of IL4I1, and activation by p53 and inhibition by NF-κB of CDKN1A and SERPINE1. On the other hand, radiation-enhanced binding of both p53 and RelA was observed in a putative regulatory region of the RRAD gene whose expression was downregulated both by TP53 and RELA silencing, which suggested a possibility of direct (co)activation by both factors.ConclusionsFour new candidates for genes directly co-regulated by NF-κB and p53 were revealed.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5211-y) contains supplementary material, which is available to authorized users.

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“…Sequencing reads were downloaded and aligned to human genome hg19 using Bowtie 2.2.9 [131]. Aligned reads were subjected to peak calling using MACS and annotated using Homer following methods published previously [132][133][134][135][136]. Peak information of the putative targets was analyzed by the BETA algorithm in Cistrome analysis pipeline (http://cistrome.org/ap/root) [137].…”

Section: Enrichment Analysis Of Transcription Proteins Binding Sitesmentioning

confidence: 99%

Proteome and Phosphoproteome Changes Associated with Prognosis in Acute Myeloid Leukemia

Aasebø

Berven

Bartaula-Brevik

et al. 2020

Cancers

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Acute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly. Although complete remission (CR) is achieved for the majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has become of major clinical interest in AML. We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify the protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a five-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells. This suggests that therapy against the upregulated kinases could also target the factors inducing their upregulation rather than their activity. This study, therefore, presents markers that could help predict AML relapse and direct therapeutic strategies.

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Pro-inflammatory cytokine and high doses of ionizing radiation have similar effects on the expression of NF-kappaB-dependent genes

Cited by 28 publications

References 56 publications

The number of titrated microRNA species dictates ceRNA regulation

The number of titrated microRNA species dictates ceRNA regulation

RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation

Proteome and Phosphoproteome Changes Associated with Prognosis in Acute Myeloid Leukemia

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