Transactivation of proenkephalin gene by HTLV-1 tax1protein in glial cells: Involvement of Fos/Jun complex at an AP-1 element in the proenkephalin gene promoter

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Abstract
The human T-cell lymphotropic virus type 1 (HTLV-1), an etiologic agent for adult T-cell leukemia, is strongly associated with tropical spastic paraparesis, a chronic neurological disease. The HTLV-1 genome encodes a protein, tax1, an autoregulator of enhanced viral RNA transcription, that also transactivates/represses certain cellular gene promoters. Enkephalins are opioid peptides that function as neurotransmitters and neuroimmunomodulators. We earlier reported that the proenkephalin gene is transactivated by tax1 protein in glial cells. The nucleotide sequence upstream of -190 base pairs in the proenkephalin gene promoter is necessary for maximal transactivation by tax1 while the sequence downstream of -190 bp confers modest activation by tax1. We investigated the cellular transcription factors in tax1 expressing glial cells that associate with the proenkephalin promoter and herein demonstrate the enhanced interaction and involvement of c-Fos/c-Jun proteins in the complexes formed at the AP-1 site. The HTLV-1 tax1 expressing stable glial cell lines produced functional tax1 protein that increased the expression of endogenous proenkephalin gene. The comparative electrophoretic mobility shift and 'supershift' analysis using specific antibodies indicated the enhanced presence of c-Fos and c-Jun proteins in the DNA: protein complex formed at the AP-1 site. The c-Fos protein expression significantly increased in the tax1 expressing glial cells. The tax1 induced c-Fos protein levels and the concurrently increased association of c-Fos/c-Jun transcription factors at the AP-1 site imply a strong functional significance in the activation of proenkephalin gene expression in tax1 expressing glial cells.

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