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

Abstract

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.

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

“…p53 knockdown, as expected, mitigates (whereas RelA silencing enhances) radiation-dependent PAI-1 expression (107). Because p300-cAMP response element binding protein-binding protein (CBP) coactivator complexes mediate expression of genes competitively regulated by both p53 and RelA, 1 model suggests that RelA interactions with p300-CBP may inhibit target gene expression, whereas binding of p53 to p300-CBP results in loss of (suppressive) NF-kB activity (107,108). Gain-offunction p53 variants also promote acquisition of the fibroproliferative phenotype by complexing with and suppressing the activity of the PAI-1-CD44-cyclin D1 transcriptional repressor Kruppel-like factor 17 (109).…”

“…Interestingly, in a different cell type, g-radiation also stimulates PAI-1 expression as well as the binding of p53 and the avian reticuloendotheliosis oncogene homolog A (RelA) (p65) to the PAI-1 gene. p53 knockdown, as expected, mitigates (whereas RelA silencing enhances) radiation-dependent PAI-1 expression (107). Because p300-cAMP response element binding protein-binding protein (CBP) coactivator complexes mediate expression of genes competitively regulated by both p53 and RelA, 1 model suggests that RelA interactions with p300-CBP may inhibit target gene expression, whereas binding of p53 to p300-CBP results in loss of (suppressive) NF-kB activity (107,108).…”

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

“…The transcription factor p53 is known to control radiation sensitivity [25,26,27,28]. Except in a few reports, p53 dysfunction has been shown to correlate with reduced radiosensitivity.…”

“…Although the relationship between p53 and the radiation response is well-known [25,26,27,28], p53 is not the only factor that controls the radiosensitivity of cells. Previous studies have suggested that 15-LOX-2 and 12-LO are also involved in regulating radiosensitivity both in head and neck and prostate cancers [22,23,24].…”

Combining CDKN1A gene expression and genome-wide SNPs in a twin cohort to gain insight into the heritability of individual radiosensitivity

“…A recent study of Price et al ( 2015 ) suggests that CDKN1A regulates Langerhans cell and could influence the response of cutaneous tumours to radiotherapy. CDKN1A abnormal expression has been reported to be associated with acute sensitivity to radiation (Amundson et al 2003 ; Badie et al 2008 ; Szołtysek et al 2018 ). In Alsbeih et al ( 2007 ), they show that individual response in CDKN1A is related to inherent radiosensitivity.…”