THE ONCOPROTEIN V-ETS IS LESS SELECTIVE IN DNA-BINDING THAN C-ETS-1 DUE TO THE C-TERMINAL SEQUENCE CHANGE

The oncogene v-ets and the proto-oncogene c-ets-1 code for members of the Ets family of transcription factors that bind to DNA motifs compri sing GGA(A/T) through the conserved Ets domain. c-Ets-1 and v-Ets are very similar, differing in sequence only at three positions. In this r eport we demonstrate that v-Ets has a less stringent target sequence r equirement than c-Ets-1. v-Ets binds strongly to a broad spectrum of D NA sequence motifs, and consequently, weaker binding sites have a much greater affinity for v-Ets than c-Ets-1. c-Ets-1 carries two inhibito ry domains: the D domain present N-terminal to the DNA binding domain and the C-terminal domain which is mutated in v-Ets. Our results show that the D domain has a stronger inhibitory effect than the C-terminal sequence. The on- and off-rates of c-Ets-1 vary greatly depending on the DNA binding sequences, in contrast to those of v-Ets. The c-Ets-1 on- and off-rates are higher with a strong site than with a weak site. Our data suggest that DNA sequences help c-Ets-1 change from a closed to an open, DNA-binding-competent structure, facilitating its binding to DNA, whereas v-Ets functions without such a process presumably bec ause its different C-terminal sequence generates a constitutively open conformation. The loss of a stringent target sequence selectivity by v-Ets suggests that it might transform cells by altering expression of tightly regulated genes with non-consensus Ets binding sites.