Abstract
BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically associated with adult T-cell leukemia (ATL). The HTLV-1 bZIP factor (HBZ), which is encoded by minus strand of provirus, is expressed in all ATL cases and supports the proliferation of ATL cells. However, the precise mechanism of growth promoting activity of HBZ is poorly understood.ResultsIn this study, we showed that HBZ suppressed C/EBPα signaling activation induced by either Tax or C/EBPα. As mechanisms of HBZ-mediated C/EBPα inhibition, we found that HBZ physically interacted with C/EBPα and diminished its DNA binding capacity. Luciferase and immunoprecipitation assays revealed that HBZ repressed C/EBPα activation in a Smad3-dependent manner. In addition, C/EBPα was overexpressed in HTLV-1 infected cell lines and fresh ATL cases. HBZ was able to induce C/EBPα transcription by enhancing its promoter activity. Finally, HBZ selectively modulated the expression of C/EBPα target genes, leading to the impairment of C/EBPα-mediated cell growth suppression.ConclusionHBZ, by suppressing C/EBPα signaling, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically associated with adult T-cell leukemia (ATL)
HTLV-1 bZIP factor (HBZ) suppresses C/EBPα signaling To investigate the effect of HBZ on the CCAAT/enhancer binding protein (C/EBP) signaling pathway, Jurkat cells were cotransfected with expression vectors of C/EBPα and HBZ along with a C/EBP-responsive reporter: C/EBP-Luc
HBZ overcame the repression of HTLV-1 viral transcription by C/EBPα (Figure 1B)
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically associated with adult T-cell leukemia (ATL). The HTLV-1 bZIP factor (HBZ), which is encoded by minus strand of provirus, is expressed in all ATL cases and supports the proliferation of ATL cells. Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) [1,2]. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the HTLV-1 genome, is expressed in all ATL cases and supports the proliferation of HTLV-1 infected cells [6,7,8]. HTLV-2, a type of retrovirus which is similar with HTLV-1, encodes an antisense protein (APH-2) using the minus strand of its genome. HBZ dysregulated multiple cellular signalings including the classical pathway of NF-κB, TGF-β, AP-1, and the Wnt pathways, which is likely to contribute to viral persistence and clonal expansion of infected cells [12,13,14,15]
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