HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling
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Qingsong Huang1,2,3,*, Zhiguo Niu2,3,*, Jingxian Han4, Xihong Liu2, Zhuangwei Lv5, Huanhuan Li2, Lixiang Yuan2, Xiangping Li6, Shuming Sun1, Hui Wang2,3 and Xinxiang Huang1
1School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
2Research Center for Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China
3Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China
4The 7th Hospital of Zhengzhou City, Zhengzhou, Henan, China
5The Third Affiliated Hospital Of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
6Luoyang Orthopedic-Traumatological Hospital, Zhengzhou, Henan, China
*These authors contributed equally to this work
Xinxiang Huang, email: firstname.lastname@example.org
Hui Wang, email: email@example.com
Keywords: HTLV-1, Tax, EGR1, NF-κB, adult T cell leukemia
Received: May 11, 2016 Accepted: February 20, 2017 Published: May 08, 2017
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.
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