HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 TAX TRANSACTIVATES THE HUMAN PROLIFERATING CELL NUCLEAR ANTIGEN PROMOTER

The human T-cell leukemia virus type 1 (HTLV-1) transforming protein, Tax, is a potent transactivator of both viral and cellular gene expres sion. The ability of Tax to transform cells is believed to depend on i ts transactivation of cellular-growth-regulatory genes. Expression of proliferating cell nuclear antigen (PCNA) is intimately linked to cell growth and DNA replication and repair. By testing a series of PCNA pr omoter deletion constructs, we have demonstrated that the PCNA promote r can be transactivated by Tax. The smallest construct that was activa ted did not include the ATF/CRE binding site at nucleotide -50, and mu tations in the ATF/CRE element in the contest of a larger promoter wer e still activated by Tax. In addition, a Tax mutant that is defective for activation of the CRE pathway retained the ability to activate the -397 promoter construct. When a series of linker scanner mutations th at span the region from nucleotide -45 to -7 were assayed, mutations i n and around a repeat sequence mere found to abolish Tax transactivati on. Multimerized copies of either half of the repeat were Tax responsi ve. A single protein complex was shown to bind specifically to the Tax -responsive region, and the binding of this complex was enhanced in th e presence of Tax. These results demonstrate that the PCNA promoter co ntains a Tax-responsive element located between nucleotides -45 and -7 whose sequence is different from those of other, previously identifie d Tax-responsive elements. The ability of Tax to activate the PCNA pro moter may play an important role in cellular transformation by HTLV-1.