DUAL CONTROL OF MYC EXPRESSION THROUGH A SINGLE DNA-BINDING SITE TARGETED BY ETS FAMILY PROTEINS AND E2F-1

NIH3T3 cells expressing a mutant colony-stimulating factor-1 receptor (CSF-1R) containing a phenylalanine for tyrosine substitution in the t yrosine kinase domain at codon 809 exhibit defective myc regulation an d do not enter S phase when stimulated by CSF-1. Enforced expression o f either ets-1 or ets-2 in these cells restores their mitogenic respon se, albeit less efficiently than myc itself, suggesting that ets prote ins may regulate c-myc expression. Ets-1 transactivates reporter genes driven by the human and mouse c-myc promoters through the binding sit e for the transcription factor E2F, the latter being required for E1A- and serum-induced c-mye expression. Analysis of E2F-1 sequences ident ified a minimal DNA binding domain that is related to those of ets pro teins. Although E2F and ets proteins interact with similar consensus D NA binding sites, in vitro binding assays revealed that E2F can bind D NA as a homodimer, whereas ets proteins bind these sites as monomers. E2F and ets proteins do not form heterodimers in vitro and do not tran sactivate c-mye synergistically. Thus, E2F-1 and ets family members ma y independently regulate c-mye transcription through the same binding site at different times following growth factor stimulation.