TRANSACTIVATION OF PROENKEPHALIN GENE BY HTLV-1 TAX(1) PROTEIN IN GLIAL-CELLS - INVOLVEMENT OF FOS JUN COMPLEX AT AN AP-1 ELEMENT IN THE PROENKEPHALIN GENE PROMOTER/

The human T-cell lymphotropic virus type 1 (HTLV-1), an etiologic agen t for adult T-cell leukemia, is strongly associated with tropical spas tic paraparesis, a chronic neurological disease. The HTLV-1 genome enc odes a protein, tax(1), an autoregulator of enhanced viral RNA transcr iption, that also transactivates/represses certain cellular gene promo ters. Enkephalins are opioid peptides that function as neurotransmitte rs and neuroimmunomodulators. We earlier reported that the proenkephal in gene is transactivated by tax(1) protein in glial cells. The nucleo tide sequence upstream of -190 base pairs in the proenkephalin gene pr omoter is necessary for maximal transactivation by tax(1) while the se quence downstream of -190 bp confers modest activation by tax(1). We i nvestigated the cellular transcription factors in tax(1) expressing gl ial cells that associate with the proenkephalin promoter and herein de monstrate the enhanced interaction and involvement of c-Fos/c-Jun prot eins in the complexes formed at the AP-1 site. The HTLV-1 tax(1) expre ssing stable glial cell lines produced functional tax(1) protein that increased the expression of endogenous proenkephalin gene. The compara tive electrophoretic mobility shift and 'supershift' analysis using sp ecific antibodies indicated the enhanced presence of c-Fos and c-Tun p roteins in the DNA: protein complex formed at the AP-1 site. The c-Fos protein expression significantly increased in the tax(1) expressing g lial cells. The tax(1) induced c-Fos protein levels and the concurrent ly increased association of c-Fos/c-Tun transcription factors at the A P-1 site imply a strong functional significance in the activation of p roenkephalin gene expression in tax(1) expressing glial cells.