Comparison of the DNA binding specificity and function of v-ErbA and thyroid hormone receptor alpha 1

Abstract

The oncoprotein v-ErbA is a mutated version of thyroid hormone receptor alpha 1. Although the basis for the oncogenic action of v-ErbA is unknown, expression of this protein is known to inhibit thyroid hormone and retinoic acid induction of target genes. The DNA binding domain of v-ErbA differs from that of thyroid hormone receptor alpha 1 in two amino acids felt to be crucial for determining the specificity of DNA binding. However, the DNA binding properties of v-ErbA have not been examined independent of a comparison of binding to already known thyroid hormone response elements. In the current studies a non-biased strategy was used to select from a pool of random DNA those sequences that bind v-ErbA with high affinity. The highest affinity binding sequence was identified as the decamer 5'-T(A/G)AGGTCACG, which is closely related to the optimal thyroid hormone receptor alpha 1 binding sequence, TAAG-GTCA. Transfection studies demonstrate that among equal thyroid hormone responsive elements, those that contain the optimal v-ErbA consensus will be repressed by v-ErbA in preference to those that do not. These studies indicate that v-ErbA and thyroid hormone receptor alpha 1 regulate overlapping sets of response elements, and that all sequences that are highly responsive to thyroid hormone are not necessarily responsive to v-ErbA.