HTLV-1 TAX1 AS AN EXTRACELLULAR CYTOKINE

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Human T-cell lymphotropic virus type I (HTLV-I) is associatred with two human diseases, adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM). HTLV-I Tax1 is released from infected lymphocytes and functions as an extracellular cytokine to stimulate gene expression in, and proliferation of, uninfected lymphocytes. The human parathyroid hormone related protein (PTHrP) gene has been analyzed in HTLV-I infected and uninfected cells as a target cellular gene for intracellular or extracellular Tax1. The analysis of PTHrP gene expression is important since humoral hypercalcemia of malignancy (HHM) is closely linked to PTHrP synthesis and secretion. Several types of human cancers, including ATL, are frequently associated with hypercalcemia. PTHrP shares with the parathyroid hormone (PTH) the ability to interact with the PTH/PTHrP receptor and, consequently, to induce bone absorption and increased calcium reabsorption in the kidney, which eventually results in an increased calcium level in the blood. The PTHrP promoter is stimulated by several extracellular cytokines and growth factors. The transcription factor Ets1 is the primary target for Tax1 transactivation of the PTHrP promoter. In order to determine the mechanism by which Tax1 cooperates with Ets1, a Gal4/Tax1 fusion protein was tested for its ability to transactivate the PTHrP promoter containing a Gal4 binding site in the proximity of the Ets1 binding site. Gal4/Tax1 was able to transactivate the PTHrP/Gal4 promoter in the absence of Ets1. Furthermore, the addition of Ets1 did not further increase the activity of the promoter in the presence of Tax1. In contrast, Ets1 was required for Gal4/Tax1 transactivation of the wild type PTHrP promoter. This suggests that Tax1 may bind to Ets1 to anchor itself to the DNA to be able to interact with factors of the basal machinery. In agreement with this hypothesis, Ets1 was observed to physically interact with Tax1 in vitro as shown by gel shift assays and in vivo as shown by the two-hybrid system in yeast. The domain of Ets1 and Tax1 that mediate the Tax1/Ets1 interaction are being analyzed.