THE E47 TRANSCRIPTION FACTOR BINDS TO THE ENHANCER SEQUENCES OF RECOMBINANT MURINE LEUKEMIA VIRUSES AND INFLUENCES ENHANCER FUNCTION

The genomes of most recombinant murine leukemia viruses (MuLVs) inheri t pathogenic U3 region sequences from the endogenous xenotropic provir us Bxv-1. However, the U3 regions of about one-third of recombinant Mu LVs from CWD mice, such as CWM-T15, have nonecotropic substitutions th at are probably derived from an endogenous polytropic provirus. The CW M-T15 U3 region sequences contain five nucleotide substitutions compar ed with the less pathogenic sequences of the endogenous ecotropic viru s parent, Emv-1. Three of these substitutions are located immediately 3' of the enhancer core, and two form part of an E-box motif that is a lso found in the Bxv-2 sequence. A series of electromobility shift ass ays revealed that nuclear extracts from S194 cells and the basic helix -loop-helix transcription factor E47 could distinguish between oligonu cleotides that contained the core region sequences of CWM-T15 or Emv-1 . The E47 homodimers appeared to bind to the CWM-T15 E box motif and w hen expressed at high levels in cells transactivated the CWM-T15 but n ot the Emv-1 enhancer. Taken together, these results suggest that E47 or related basic helix-loop-helix proteins that are expressed in lymph oid cells bind to and transactivate the CWM-T15 enhancer in vivo. This transactivation may explain why the CWM-T15 and Bxv-1 U3 regions acce lerate the onset of lymphoid neoplasms and why related enhancer core r egion sequences are preferentially incorporated into the genomes of re combinant MuLVs and are found in other leukemogenic mammalian retrovir uses.