STIMULATION OF ALPHA-1(I) PROCOLLAGEN GENE-EXPRESSION IN NIH-3T3 CELLS BY THE HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 (HTLV-1) TAX GENE

The mechanisms that regulate the expression of genes encoding extracel lular matrix proteins in fibroblasts and other mesenchymal cells have remained elusive. Studies from several laboratories have indicated tha t Tax, a trans-regulatory protein from the human T cell leukemia virus type I not only augments viral gene expression but also triggers the expression of various cellular genes. Here, we examined the hypothesis that the expression of collagen genes may also be modulated by Tax, N IH-3T3 cells were simultaneously transfected with a Tax expressor plas mid and a chimeric construct containing regulatory sequences (-804 to +42 bp) of the alpha 1(I) procollagen gene (COL1A1) promoter, The resu lts indicated that the promoter activity of the -804 to +42 bp COL1A1 fragment increased up to 12-fold in cells expressing Tax. Deletion ana lysis revealed that the region of COL1A1 encompassing nucleotides -174 to -84 contained the Tax-responsive elements. A gene segment encompas sing nucleotides -187 to -67, which contained this region, proved suff icient to confer Tax inducibility (2.5-fold) to a herpes simplex virus thymidine kinase promoter. Stably transfected NIH-3T3 cell clones tha t constitutively produce Tax displayed elevated levels of alpha 1(I) p rocollagen and fibronectin transcripts and increased production and ac celerated processing of type I procollagen. These findings suggest tha t retroviral proteins may be involved in the pathogenesis of idiopathi c diseases accompanied by collagen overproduction.