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Characterization of the DNA-Binding and Dominant Negative Activity of v-erbA Homodimers

Division of Endocrinology and Metabolism (J.S.S.) University of Mississippi Medical Center and G. V. (Sonny) Montgomery Veterans Administration Medical Center (J.S.S.) Jackson, Mississippi 39216
Division of Endocrinology and Metabolism (R.J.K.), University of Michigan Medical Center Ann Arbor, Michigan 48109-0678

The oncoprotein v-erbA is a mutated form of thyroid hormone receptor 1 that is virtually incapable of binding T₃. V-erbA is a dominant repressor of transcription induced by thyroid hormone receptors and retinoic acid receptors; however, the genetic targets of v-erbA that lead to oncogenesis are not known. Although v-erbA can bind as monomers and dimers to DNA containing the consensus sequence AGGTCA arranged as direct, inverted, or everted repeats, it is not known which sequence represents the optimal v-erbA-binding site. Determination of the DNA recognition properties of v-erbA would allow a better understanding of the repressor activity of this oncoprotein. The current studies, by using a random DNA selection strategy, have determined that the imperfect everted repeat 5'-TGACC(T/C)NT(A/G)AGGTCAC is the optimal v-erbA homodimer-binding site, where N represents any di- or trinucleotide. Functional studies show that everted repeats containing this sequence are substantially more potent v-erbA response elements than direct or inverted repeats, even though many classic T₃ response elements are direct repeats. Thus, v-erbA represses only a subset of T₃ response elements. In a similar fashion, v-erbA was found to repress a subset of vitamin D response elements. Of general interest, the data indicate that the two molecules of a transcription factor homodimer do not necessarily have identical DNA-binding specificities.

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