Transcription factor Ets-2 regulates the expression of key lymphotropic factors
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ORIGINAL ARTICLE
Transcription factor Ets‑2 regulates the expression of key lymphotropic factors Panagiota Davoulou1 · Ioanna Aggeletopoulou1 · Ioannis Panagoulias1 · Tassos Georgakopoulos1 · Athanasia Mouzaki1 Received: 18 March 2020 / Accepted: 25 September 2020 © Springer Nature B.V. 2020
Abstract Transcription factor Ets-2 downregulates the expression of cytokine genes and HIV-1 in resting T-cells. Herein, we studied whether Ets-2 regulates the expression of lymphotropic factors (LFs) NFAT2, NF-κΒ/p65, c-Jun, c-Fos, which regulate the activation/differentiation of T-cells, and kinase CDK10, which controls Ets-2 degradation and repression activity. In silico analysis revealed Ets-2 binding sites on the promoters of NFAT2, c-Jun, c-Fos. The T-cell lines Jurkat (models T-cell signaling/activation) and H938 (contains the HIV-1-LTR) were transfected with an Ets-2 overexpressing vector, in the presence/ absence of mitogens. mRNA and protein levels were assessed by qPCR and Western immunoblotting, respectively. Ets-2 overexpression in unstimulated Jurkat increased NFAT2 and c-Jun mRNA/protein, c-Fos mRNA and NF-κΒ/p65 protein, and decreased CDK10 protein. In unstimulated H938, Ets-2 upregulated NFAT2, c-Jun and CDK10 mRNA/protein and NF-κΒ/p65 protein. In stimulated Jurkat, Ets-2 increased NFAT2, c-Jun and c-Fos mRNA/protein and decreased CDK10 mRNA/protein. In stimulated H938 Ets-2 increased NFAT2, c-Jun and c-Fos protein and reduced CDK10 protein levels. Furthermore, Ets-2 overexpression modulated the expression of pro- and anti-apoptotic genes in both cell lines. Ets-2 upregulates the expression of key LFs involved in the activation of cytokine genes or HIV-1 in T-cells, either through its physical interaction with gene promoters or through its involvement in signaling pathways that directly impact their expression. The effect of Ets-2 on CDK10 expression in H938 vs Jurkat cells dictates that, additionally to Ets-2 degradation, CDK10 may facilitate Ets-2 repression activity in cells carrying the HIV-1-LTR, contributing thus to the regulation of HIV latency in virus-infected T-cells. Keywords T-cells · HIV-1 · NFAT2 · NF-κβ p65 · c-Jun · c-Fos · CDK10
Introduction Ets-2 belongs to the ETS family of transcription factors that are highly conserved among different species, the abnormal expression of which has been associated with tumorigenesis and malignant transformation [1–3]. The Ets-2 gene is localized on human chromosome 21 and codes for a 58 kDa protein. Ets-2 functions either as an activator or repressor of transcription and is involved in diverse biological functions, such as cell mitosis, development, differentiation, apoptosis and regulation of immunity * Athanasia Mouzaki [email protected] 1
Laboratory of Immunohematology, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26500 Patras, Greece
[4]. Ets-2 binds to a core GGAA/T consensus sequence through a conserved winged helix-turn-helix DNA-binding domain. Furthermore, Ets-2, in common with other ETS m
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