Transactivation of the proenkephalin gene promoter by the Tax1 protein of human T-cell lymphotropic virus type I.

Human T-cell lymphotropic virus type I (HTLV-I), an etiologic agent for adult T-cell leukemia, is strongly associated with certain neurological diseases. The HTLV-I genome encodes a protein, Tax1, that transactivates viral gene transcription. CD4-positive T helper lymphocytes express the proenkephalin gene, and enkephalins have been implicated as neuroimmunomodulators. We have investigated the effect of Tax1 on the proenkephalin gene promoter in C6 rat glioma cells and demonstrated its transactivation. Analysis using 5' deletion mutants of the promoter region showed that sequences upstream of base pair -190 are necessary for maximal transactivation. Forskolin, a cAMP modulator, synergistically increased Tax1-mediated transactivation of the proenkephalin promoter. Neither Tax1 transactivation alone nor Tax1/cAMP synergism exclusively involved cAMP-responsive elements. Endogenous proenkephalin gene expression increased in Tax1-expressing C6 cells. Since HTLV-I infects lymphocytes, which express proenkephalin mRNA, Tax1 transregulation of proenkephalin expression may provide bidirectional communication between the nervous and immune systems in HTLV-I-related diseases.