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 comprising 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 report we demonstrate that v-Ets has a less stringent target sequence requirement than c-Ets-1. v-Ets binds strongly to a broad spectrum of DNA sequence motifs, and consequently, weaker binding sites have a much greater affinity for v-Ets than c-Ets-1. c-Ets-1 carries two inhibitory 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 because 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.
Hahn
S L
SL
LGME-CNRS and U184-INSERM, Institut de Chimie Biologique, Faculté de Médecine, Strasbourg, France.
Wasylyk
B
B
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D015682:Retroviridae Proteins, Oncogenic / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors
D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; C050379:oncogene proteins v-ets; D004247:DNA