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Thyroid hormone receptor transcriptional activity is potentially autoregulated by truncated forms of the receptor

ErbA/thyroid hormone receptor is a nuclear receptor that can affect transcription from promoters containing a thyroid hormone response element (TRE) in a thyroid hormone (T3)-dependent manner. We reported earlier that the thyroid hormone receptor is expressed in embryonic avian erythroid cells as a nested set of four proteins with a common C terminus. The full-length receptor is capable of both high-affinity binding to thyroid hormone and specific binding to DNA. We now report that the two smallest ErbA forms, which contain the hormone-binding domain but lack the N-terminal DNA-binding domain, have the same affinity for T3 as does full-length ErbA but are incapable of specific DNA binding. In transactivation assays, these N-terminally truncated proteins are able to specifically suppress both transcriptional repression and hormone-dependent transcriptional activation by the full-length ErbA. We also find that retinoic acid-dependent transactivation by retinoic acid receptors is inhibited by the truncated ErbA proteins. Furthermore, the smaller ErbA forms inhibit binding to TREs by full-length ErbA in vitro. Results from experiments involving site-specific mutagenesis of a conserved region within the hormone-binding domain of the smaller ErbA proteins indicate that the suppressive effect of the smaller receptor forms is independent of hormone binding and that this region is important in mediating protein-hormone as well as protein-protein interactions. We have also found that full-length ErbA homodimers can be detected only in the presence of a specific DNA-binding site. However, no association between full-length and the N-terminally truncated non-DNA-binding ErbA proteins could be detected, indicating that the complex either is unstable or does not form. Our results suggest that inhibition of receptor function occurs through transient formation of heterodimers which lack DNA-binding activity or by competition for factors which positively affect DNA binding by the full-length protein. This finding raises the possibility that thyroid hormone receptor transcriptional activity is autoregulated by means of alternative receptor translation products acting in a dominant negative manner.