Overexpression of the immediate early response 5 gene increases the radiosensitivity of HeLa cells

Ding, Kun; Yang, Fen; Jiang, Hui‐Qing; Yuan, Zengqiang; Yin, Lingling; Liu, Dong; Cui, Wei; Gou, Qiao; Liu, Xiaodan; Wu, Yumei; Jiang, Xingming; Zhang, Xin; Zhou, Ping‐Kun; Yang, Chen

doi:10.3892/ol.2019.10590

Cited by 4 publications

(3 citation statements)

References 23 publications

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“…Growth-promoting stimuli and genotoxic factors such as radiation can activate IER5 expression Shi et al, 2016). IER5 may influence cell proliferation along with survival in response to ionizing radiation and thermal stress by regulating cell cycle checkpoints (Ding et al, 2009(Ding et al, , 2019.…”

Section: Discussionmentioning

confidence: 99%

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

Wang

Zeng

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveImmediate early response 5 (IER5) plays a core role in cell cycle and response to irradiation. However, its role in glioma remains unclear. We aimed to evaluate its prognostic significance in glioma based on The Cancer Genome Atlas data resource.MethodsThe Kruskal–Wallis test, Wilcoxon signed-rank test, and logistic regression were employed to explore the relationship between IER5 expression and clinicopathological features. Kaplan–Meier and Cox regression analyses were implemented to investigate the relationship of IER5 with prognosis. A nomogram to estimate the impact of IER5 on prognosis was created based on the Cox multivariate data. We performed gene set enrichment analysis (GSEA) to determine the key signaling cascades associated with IER5. Immunohistochemistry was performed to examine IER5 expression in a tissue microarray (TMA) of glioma samples.ResultsImmediate early response 5 gene expression was elevated in glioma patients. The level of IER5 was significantly correlated with WHO grade [OR = 6.71 (4.34–10.68) for G4 vs. G2 and G3], IDH (isocitrate dehydrogenase enzyme) status [OR = 13.35 (8.92–20.46) for wild-type (WT) vs. mutated (Mut)], epidermal growth factor receptor status [OR = 8.42 (4.32–18.43) for Mut vs. WT], age [OR = 0.27 (0.18–0.41) for ≤ 60 years vs. >60 years], and histological type [OR = 7.13 (4.63–11.31] for glioblastoma vs. astrocytoma, oligoastrocytoma, and oligodendroglioma). Univariate analyses revealed that high IER5 expression was linked to short overall survival (OS) [hazard ratio (HR): 3.747; 95% confidence interval (CI): 2.847–4.933; and P < 0.001]. High IER5 expression was linked to poor OS in multivariate analyses (HR: 2.474; 95% CI: 1.552–3.943; and P < 0.001). TMA results showed that high IER5 protein levels were related to short OS (HR: 1.84; 95% CI: 1.10–3.07; and P = 0.021) and poor disease-specific survival (HR: 1.82; 95% CI: 1.09–3.04; and P = 0.023). GSEA showed that many tumor related pathways were enriched differentially in the IER5-high expression group. The C-index and calibration plots of the nomogram showed an effective estimation performance in glioma patients.ConclusionHerein, we established that IER5 plays a critical role in glioma progression and prognosis, which might be an important biomarker for the prognosis of glioma patients.

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Section: Discussionmentioning

confidence: 99%

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

Wang

Zeng

et al. 2021

Front. Cell Dev. Biol.

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“…In S. pombe, previous studies have found that high dNTP levels can lead to increased DNA damage sensitivity and slow progression through S-phase (Fleck et al, 2013;Pai and Kearsey, 2017). A recent study has suggested a role for PAF1 in attenuating radiosensitivity by inhibiting immediate-early response 5 (IER5) transcription, which is involved in cell cycle regulation (Ding et al, 2019;Zheng et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

R-loop-induced p21 expression following CDC73, CTR9, and PAF1 loss protects cancer cells against replicative catastrophe following WEE1 inhibition

Bijsterveldt

Landsverk

Näshe

et al. 2021

Preprint

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WEE1 inhibitors have now advanced into clinical studies as monotherapy or in combination with chemoradiotherapy in TP53, RAS, BRAF, and SETD2 mutation carriers across several tumour types, yet mechanisms of resistance are still poorly understood. Here, we further elucidate the mechanisms by which AZD1775, the most potent WEE1 inhibitor, kills cells and reveal additional genetic interactions that can result in resistance, but could be used to optimise its clinical utility. We identified RNA Polymerase II-associated factor 1 (PAF1) complex members, CDC73, CTR9, and PAF1 as major determinants of WEE1-inhibitor sensitivity in isogenic SETD2-positive and negative cell lines. PAF1-knockdown cells resist higher doses of the WEE1 inhibitor, which we show is due to reduced DNA damage induction (γH2AX) and delayed G1 checkpoint activation, ultimately protecting cells against replicative catastrophe. Investigations into the molecular mechanisms responsible for PAF1-mediated resistance identify involvement of R-loops and subsequent activation of the cyclin-dependent kinase inhibitor p21Cip1/Waf1, which in addition to causing prolonged G1 arrest in the following cell cycle, also regulates CDK activity, therefore limiting replication. These results provide evidence that the PAF1 complex and p21 are important regulators of proliferation under increased DNA replication stress and their expression levels might be useful biomarkers to predict clinical response to WEE1 inhibitors and other ribonucleotide reductase inhibitors.

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“…IER2 participates in the regulation of normal embryonic development, cell motility, senescence and death [29][30][31][32][33]. The IER5 gene is a target of HSF1 and the tumour suppressor p53, and IER5 expression is associated with proteotoxic and genotoxic stress responses as well as cell proliferation [22,23,[34][35][36].…”

Section: Introductionmentioning

confidence: 99%

PP2A‐B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle‐related genes

2022

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The retinoblastoma (RB) tumour suppressor protein regulates cell proliferation, motility, differentiation and apoptosis. The phosphorylation state of RB is modulated by kinases and phosphatases, and RB exhibits phosphorylation‐sensitive interactions with E2F family transcription factors. Here, we characterize RB dephosphorylation by protein phosphatase 2A (PP2A). The growth factor‐inducible immediate early response (IER) proteins IER2 and IER5 possess an adapter‐like function in which IER proteins bind to both PP2A and its target proteins and enhance PP2A activity towards the proteins. IER2 interacts with RB and facilitates dephosphorylation of RB at T821/T826 by PP2A. In IER2 knockdown cells, elevated phosphorylation of RB resulted in reduced binding of RB to the promoters and derepression of cyclin D1 and p21. IER5 binds to both RB and RB‐like 1 (p107/RBL1), enhances dephosphorylation of these proteins by PP2A and represses the expression of various cell cycle‐related genes. However, IER2‐regulated dephosphorylation at T821/T826 is not necessary for the repression function of RB in cell mobility‐related gene expression. Our data identify PP2A adapter proteins as critical regulators of RB family proteins and suggest that the phosphorylation status of RB differentially affects gene expression.

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Overexpression of the immediate early response 5 gene increases the radiosensitivity of HeLa cells

Cited by 4 publications

References 23 publications

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

R-loop-induced p21 expression following CDC73, CTR9, and PAF1 loss protects cancer cells against replicative catastrophe following WEE1 inhibition

PP2A‐B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle‐related genes

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