Tax 1-Independent Induction of Vascular Endothelial Growth Factor in Adult T-Cell Leukemia Caused by Human T-Cell Leukemia Virus Type 1

Abstract

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). Elevated expression of vascular endothelial growth factor (VEGF) in ATL patients is associated with leukemic cell invasion and infiltration in different organs. The regulatory protein Tax 1 encoded by HTLV-1 plays a pivotal role in T-cell transformation by deregulating the function and expression of several cellular factors. In the present study, we examined the effect of Tax 1 on VEGF expression at transcriptional and posttranscriptional levels in order to elucidate the regulatory mechanisms involved. Using functional assays, we demonstrate that Tax 1 downregulates the VEGF promoter through a cluster of Sp1 sites located close to the transcriptional start site. Using gel mobility shift assays, we show that Tax 1 reduced Sp1:DNA complex formation. We demonstrate that the level of secreted VEGF was significantly lower in Tax 1-transfected 293T cells compared to nontransfected cells, which is consistent with the observed downregulatory effect of Tax 1 at the transcription level. We showed that VEGF was secreted by HTLV-1-transformed and nontransformed cells, irrespective of Tax 1 expression. Overall our data indicate that, contrary to a previous report, Tax 1 downregulates VEGF expression and suggest there are Tax 1-independent mechanisms of VEGF activation in ATL.

Antitumor effects of bevacizumab in a microenvironment‐dependent human adult T‐cell leukemia/lymphoma mouse model

“…In this study, most primary ATL cases (22/23), and all of the established cell lines tested (7/7), were positive for VEGF-A. These results are consistent with data from other investigators (16,18,19). Thus, the VEGF-A produced by ATL cells is likely to play an important role in the pathogenesis of ATL.…”

Viruses as key regulators of angiogenesis

“…Few data are available on the underlying molecular mechanisms behind these findings. The viral transcriptional activator protein Tax was proposed to be sufficient for VEGF up‐regulation , but these findings were later contradicted . Thus, more research is needed to identify the viral factors implicated in angiogenesis stimulation by HTLV‐1.…”

Cysteine-rich intestinal protein 2 ( CRIP2 ) acts as a repressor of NF-κB–mediated proangiogenic cytokine transcription to suppress tumorigenesis and angiogenesis

“…The promoter region of the proangiogenesis cytokines IL-6 and VEGF was cloned into pGL3-basic vector as described previously (20,21), The IL-8 promoter plasmids pGL-IL-8-54 and -152 were described previously (33). Luciferase activity was measured 48 h after transfection with the Promega Dual-Luciferase Reporter assay system according to the manufacturer's instructions.…”

“…The promoter regions of IL-6 and VEGF were cloned in the pGL3 vector (20,21). Our luciferase reporter assay found significantly reduced promoter activity of the proangiogenesis proteins IL-6 and VEGF by CRIP2 expression (Fig.…”