Abstract
Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.
Highlights
Adult T-cell leukemia/lymphoma (ATL) is characterized by the malignant proliferation of CD4+ T lymphocytes infected with human T cell leukemia virus type 1 (HTLV-1) [1, 2]
Early growth response protein 1 (EGR1) mRNA and protein levels, and Human T cell leukemia virus type 1 (HTLV-1) Tax protein levels were upregulated in both cell lines (Figure 1E–1F), indicating that early infection induced EGR1 expression
Persistent activation of the nuclear factor-κB (NF-κB) pathway induced by HTLV-1 Tax is the main cause of T cell transformation and adult T cell leukemia (ATL) [27, 28], and Tax alone can induce transcriptional changes in target T cells [27, 29, 30]
Summary
Adult T-cell leukemia/lymphoma (ATL) is characterized by the malignant proliferation of CD4+ T lymphocytes infected with human T cell leukemia virus type 1 (HTLV-1) [1, 2]. HTLV-1 viral proteins, especially Tax, modulate cellular gene expression through the cyclic AMP responsive element binding protein/activating transcription factors (CREB/ATF)-, serum response factor (SRF)- and nuclear factor-κB (NF-κB)-associated pathways [3]. NF-κB activity is tightly controlled and is only transiently elevated upon stimulation in normal T cells, but is constitutively activated in HTLV-1-infected T cells [3]. Tax-mediated constitutive activation of NF-κB signaling is essential for HTLV-1 infection-induced T cell transformation [4]. To study the roles of HTLV-1 Tax in ATL, we stably expressed Tax in Jurkat cells (referred to hereafter as TaxP cells). Genome-wide screens revealed a number of genes highly expressed in TaxP cells, including early growth response factor 1 (EGR1) [5]
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