A novel cis element mediating ligand-independent activation by c-ErbA: implications for hormonal regulation

Abstract

A novel type of hormone-responsive element (HRE) is described. Unlike classical HREs, this element, RSV-T3RE (found in Rous sarcoma virus-long terminal repeat), mediates strong activation by the c-ErbA alpha thyroid hormone (T3) receptor in the absence of T3, and addition of T3 reverses this response. Whereas both c-ErbA alpha and v-ErbA are potent ligand-independent activators through the RSV-T3RE, c-ErbA beta is not. The RSV-T3RE is recognized and activated by either c-ErbA alpha homodimers or c-ErbA alpha/retinoid X receptor (RXR) heterodimers. Ligand-independent activation by c-ErbA alpha depends on a unique N-terminal activation domain, while the C-terminal activation domain is not absolutely required. Ligand-dependent activation, on the other hand, requires the C-terminal but not the N-terminal activation domain. Upon binding to the RSV-T3RE, c-ErbA alpha assumes a different conformation than when bound to a classical T3RE. c-ErbA alpha is therefore capable of selective deployment of activation domains, dictated both by the HRE with which it interacts and by T3 binding.