A TRANSGENIC MOUSE MODEL OF TRANSACTIVATION BY THE TAX PROTEIN OF HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE

Abstract

The human T-cell lymphotropic virus type I (HTLV-I) Tax protein is a trans-regulatory protein believed to play a prominent role in the development of several HTLV-I-associated diseases. Tax regulates expression of viral as well as cellular genes by exploiting the transcriptional machinery of the host cell. A transgenic mouse model system has been established to define the full spectrum of tissues that are capable of supporting Tax-mediated transcriptional transactivation. Transgenic mice carrying the HTLV-I LTR driving expression of the Escherichia coil B-galactosidase (figal) gene were generated, and this LTR-flgal gene was transcriptionally inactive in all tissues. However, when the LTR-flgal mice were mated to transgenic mice carrying the same LTR driving expression of the HTLV-I tax gene, mice that carried both transgenes showed a restricted pattern of expression of the fig& reporter gene in salivary gland, muscle, bone, thymus, and nerve. Only a subset of cells within these tissues expressed the reporter gene. Tax transactivation of the reporter gene correlated well with proliferation of ductal epithelial cells in salivary gland and perineural fibroblasts in peripheral nerve, with atrophied muscle fibers, and osteoclasts in degenerating bone. Most importantly, this transgenic mouse model identified new sites of Tax transactivation in brain, pituitary gland, and skin. Tax-mediated Bgal activity in skin was greatly increased in response to wounding or chemical treatment with phorbol 12-myristate 13-acetate (PMA; also referred to as TPA). The TPA-induced βgal activity in skin was effectively blocked by the chemical compound curcumin. The transgenic mice described here provide a model system to explore mechanisms of transcriptional regulation of the HTLV-I LTR and to identify therapeutic strategies to target HTLV-I-induced diseases.