Tax 1-independent induction of vascular endothelial growth factor in adult T-cell leukemia caused by human T-cell leukemia virus type 1.
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.
Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
Karen M
KM
Watters
Jonathan
J
Dean
Virginie
V
Gautier
William W
WW
Hall
Noreen
N
Sheehy
D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D058969:Contactin 2; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000821:virology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
C548674:CNTN2 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D058969:Contactin 2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004247:DNA