Transactivation of human osteopontin promoter by human T-cell leukemia virus type 1-encoded Tax protein

Abstract

Osteopontin (OPN) is a cytokine that contributes substantially to the growth and metastasis in a wide spectrum of malignancies. We report here that OPN gene is transactivated by Tax protein of human T-cell leukemia virus type 1 (HTLV-1). Northern blot showed enhanced OPN gene expression in cells stably expressing Tax. Co-expression of Tax increased the reporter gene expression directed by OPN promoter. Tax-induced OPN activation was abrogated by treatment with LY294002 (PI3K inhibitor) or co-transfection with AKT siRNA, suggesting PI3K/AKT pathway is involved in Tax-mediated transactivation. Reporter assay with deletion mutants showed that the 5'-partial sequence between -765 and -660 of the OPN promoter is the region responsive to Tax, and further, disrupting the AP-1 site within this region abolished the OPN induction by Tax, indicating that Tax activation of OPN promoter is likely mediated by AP-1 site. This study suggests that OPN is one of the downstream mediators of aberrantly activated PI3K/AKT signaling by Tax, which may partially contribute to HTLV-1-associated leukemogenesis.