Abstract
An oncogenic retrovirus, human T-cell leukemia virus type I (HTLV-I), encodes an oncoprotein, Tax, which plays critical roles in leukemogenesis of adult T-cell leukemia/lymphoma (ATLL) through the pleiotropic actions such as transcriptional regulation, cell cycle control, and transformation. We have previously reported that PTEN and SHIP- 1, PIP3 inositol phosphatases that negatively regulate the PI3-kinase signaling cascade, are disrupted in ATLL neoplasias. Overactivation of PI3-kinase signaling has an essential role in onset of ATLL. We report here that both PTEN and SHIP-1 are downregulated by Tax through the NF-κB signaling pathway. Tax expression upregulated phosphorylated Akt, a downstream serine/threonine kinase in the PI3-kinase signaling cascade. Activation of NF-κB pathway also suppressed these phosphatases. An IκBΔN mutant which inhibits the activation of NF-κB prevented PIP3 phosphatase downregulation by Tax. The underlying mechanism of NF-κB mediated suppression of PIP3 phosphatases involved sequestration of the coactivator p300 by p65. These down-regulations of PIP3 phosphatases were found to be essential for the Tax-induced cell proliferation. Thus, our results suggest that HTLV-I Tax downregulates PIP3 phosphatases through the NF-κB pathway, resulting in increased activation of the PI3-kinase signaling cascade in human T-cells and contributing to leukemogenesis.