Mutant Tax Protein from Bovine Leukemia Virus with Enhanced Ability To Activate the Expression of c -fos

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Abstract
Bovine leukemia virus (BLV) is the etiologic agent of enzootic bovine leukosis. We previously identified several mutants of the BLV Tax protein with an ability to transactivate transcription via the BLV enhancer that is significantly greater than that of the wild-type Tax protein. Moreover, the mutant proteins also activated other viral enhancers, such as the enhancer of human T-cell leukemia virus type 1, which cannot be activated by wild-type BLV Tax. In this study, we demonstrated that the mutant proteins but not wild-type protein activate the upstream sequence of the human c -fos gene, which contains two major cis -acting elements, the CArG box and cyclic AMP-responsive element (CRE) motif. The mutant protein also strongly increased levels of endogenous c- fos mRNA in both human and bovine cell lines. On the other hand, the wild-type Tax protein has no activity to activate the expression of human c- fos , indicating that wild-type BLV Tax might discriminate between human and bovine c- fos promoter sequences. Deletion and point-mutational analysis of the cis -acting elements revealed that both the CArG box and the CRE motif were indispensable for the activation of c- fos by the mutant BLV Tax protein. Our results suggest that the mutant BLV Tax proteins might not only have the ability to enhance the production of virus particles but might also have increased ability to induce leukemia.