COMPARISON OF THE DNA-BINDING SPECIFICITY AND FUNCTION OF V-ERBA AND THYROID-HORMONE RECEPTOR ALPHA-1

The oncoprotein v-ErbA is a mutated version of thyroid hormone recepto r alpha 1. Although the basis for the oncogenic action of v-ErbA is un known, 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 a mino acids felt to be crucial for determining the specificity of DNA b inding. However, the DNA binding properties of v-ErbA have not been ex amined independent of a comparison of binding to already known thyroid hormone response elements. In the current studies a non-biased strate gy was used to select from a pool of random DNA those sequences that b ind v-ErbA with high affinity. The highest affinity binding sequence w as identified as the decamer 5'-T(A/G)AGGTCACG, which is closely relat ed to the optimal thyroid hormone receptor alpha 1 binding sequence, T AAG-GTCA. Transfection studies demonstrate that among equal thyroid ho rmone responsive elements, those that contain the optimal v-ErbA conse nsus will be repressed by v-ErbA in preference to those that do not. T hese studies indicate that v-ErbA and thyroid hormone receptor alpha 1 regulate overlapping sets of response elements, and that all sequence s that are highly responsive to thyroid hormone are not necessarily re sponsive to v-ErbA.