HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 TAX ACTIVATES TRANSCRIPTION OF THEHUMAN FRA-1 GENE THROUGH MULTIPLE CIS-ELEMENTS RESPONSIVE TO TRANSMEMBRANE SIGNALS

We have shown that Tax1 of human T-cell leukemia virus type 1 stimulat es the expression of several cellular immediate-early genes (M. Fujii, T. Niki, T. Mori, T. Matsuda, M. Matsui, N. Nomura, and M. Seiki, Onc ogene 6:1023-1029, 1991). In this study, the 5'-flanking region of the human fra-1 gene, which is a Tax1-inducible fos-related gene, was iso lated and Tax1 or serum-responsive cis elements were analyzed to obtai n further insight into the mechanism of Tax1 action. The 62-bp sequenc e starting 46 nucleotides upstream from the translation initiation sit e showed 71% homology with the sequence surrounding the TATA box of th e c-fos promoter. Regulatory motifs identified in the c-fos promoter, such as an Ets-binding site, E boxes, a CArG box, c-fos AP-1 sites, an d two retinoblastoma control elements, were also found upstream of the c-fos homology region. A 502-bp fragment containing these motifs medi ated transcriptional activation by Tax1 or by serum in a transient tra nsfection assay. Three independent Tax1-responsive regions (TRRs) were identified, and mutations in each revealed that one of the retinoblas toma control elements in TRR1 and the c-fos AP-1 sites in TRR2 and TRR 3 were essential for the activation. Although TRR2 contains a CArG box -like sequence, it was a weak binding site for p67SRF, if it bound at all, and was not required for activation. All three TRRs could also me diate the signals stimulated by serum. Thus, Tax1 appears to activate fra-1 gene expression by means of a part of the cellular machinery sim ilar to that which mediates growth signals.