Mutations in the estrogen receptor ligand binding domain discriminate between hormone-dependent transactivation and transrepression
Valentine, J.E.; Kalkhoven, E.; White, R.; Hoare, S.; Parker, M.G.
Journal of Biological Chemistry 275(33): 25322-25329
2000
ISSN/ISBN: 0021-9258 PMID: 10840033 DOI: 10.1074/jbc.m002497200
Accession: 011030811
The estrogen receptor (ER) suppresses transcriptional activity of the RelA subunit of nuclear factor-kappaB in a hormone-dependent manner by a mechanism involving both the receptor DNA binding domain and ligand binding domain (LBD). In this study we examine the role of the ER LBD in mediating ligand-dependent RelA transrepression. Both ERalpha and ERbeta inhibit RelA in response to 17beta-estradiol but not in the presence of antihormones. We have identified residues within the ERalpha LBD that are responsible for receptor dimerization and show that dimerization is necessary for transactivation and transrepression. Moreover we have generated mutant receptors that have lost their ability to inhibit RelA but retain their capacity to stimulate transcription and conversely mutants that are transcriptionally defective but capable of antagonizing RelA. Overexpression of p160 and cAMP-response element-binding protein-binding protein/p300 co-activators failed to relieve repression of RelA, which is consistent with the demonstration that RelA inhibition can occur independently of these co-activators. These findings suggest it is unlikely that sequestration of these cofactors required for ER transcriptional activation can account for hormone-dependent antagonism of RelA. The identification of ER mutants that discriminate between transactivation and transrepression implies that distinct surfaces within the LBD are involved in mediating these two receptor functions.