Roles of v-erbA homodimers and heterodimers in mediating dominant negative activity by v-erbA

Paul M. Yen, Masato Ikeda, Jill H. Brubaker, Marc Forgione, Akira Sugawara, William W. Chin

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36 Citations (Scopus)

Abstract

v-erbA, a viral oncogenic homolog of thyroid hormone receptor (TR), blocks the effect of T3 in TR-mediated transcription. The mechanism(s) for this dominant negative effect by v-erbA on TRs is unknown but may involve competition between v-erbA and TR-containing complexes for binding to thyroid hormone response elements (TREs) and/or protein-protein interactions between v-erbA and TR. To investigate these potential mechanisms, we used the electrophoretic mobility shift assay to compare in vitro translated v-erbA and TRα binding to two TREs-chick lysozyme TRE (F2) and direct repeat TRE (DR4). v-erbA bound as a homodimer to these TREs, whereas TRα bound as a homodimer and monomer. T3 decreased TRα homodimer binding to the TREs as we reported previously; however, surprisingly, high concentrations of T3 (10- 6 M) also decreased v-erbA homodimer binding to the TREs. Additionally, v- erbA formed heterodimers with nuclear proteins such as retinoid X receptor and T3 receptor auxiliary protein as well as with TRα. These dimers remained bound to DNA in the presence of T3. Finally, v-erbA could not mediate ligand-dependent transcriptional activation even at 10-6 M T3 but could block ligand-dependent TR-mediated transactivation in co-transfection experiments. v-erbA also exhibited differential dominant negative activity on F2 and DR4 suggesting that half-site sequence and/or orientation may influence v-erbA-dominant negative activity. In sum, there are multiple v- erbA complexes that bind to TREs in the presence of T3, which all may contribute to v-erbA's dominant negative effect on TR-mediated transcription by competing with TR-containing complexes for binding to TREs.

Original languageEnglish
Pages (from-to)903-909
Number of pages7
JournalJournal of Biological Chemistry
Volume269
Issue number2
Publication statusPublished - 1994 Jan 14
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yen, P. M., Ikeda, M., Brubaker, J. H., Forgione, M., Sugawara, A., & Chin, W. W. (1994). Roles of v-erbA homodimers and heterodimers in mediating dominant negative activity by v-erbA. Journal of Biological Chemistry, 269(2), 903-909.