Estrogen receptor alpha and estrogen receptor-related receptor alpha 1 compete for binding and coactivator

The human estrogen receptor (ER alpha) and the human estrogen receptor-rela ted receptor (ERR alpha1, NR3B1a) are members of the steroid/thyroid hormon e receptor superfamily. We previously cloned an isoform of ERR alpha1 cDNA and demonstrated that ERR alpha1 binds to the human lactoferrin gene promot er and enhances estrogen responsiveness during transient transfection exper iments. In this study, we show that ERR alpha1 and ERa may interfere in eac h other's transcriptional activity by competition for binding and coactivat or. PI VP16-ERR alpha1 chimera was constructed and transiently transfected into human endometrial carcinoma HEC-1B cells. This chimera activated repor ter constructs containing the human lactoferrin gene estrogen response elem ent (ERE) and the synthetic palindromic 3X-ERE, suggesting that ERR alpha1 binds to these EREs. Therefore, ERR alpha1 can compete with ER alpha for bi nding to the same EREs. ERR alpha1 is organized into modules which include a N-terminal region that shows repression function, a Zn-finger region that binds DNA and an activation region at the C terminus. The activation funct ion of ERR alpha1 was mapped to the conserved AF2 region in the C-terminus by deletion analysis. The transactivation activity of ERR alpha1 can be enh anced by coactivator (SRC-la) and suppressed by ER alpha in the presence of estrogen, suggesting that SRC-la is required by both receptors for their a ctivity. The repression of ERR alpha1 activation function by estrogen bound ER alpha, however, could not be reversed by increasing concentration of SR C-1a in the cells. This finding is consistent with the squelching phenomeno n that exists between ER alpha and other steroid receptor family members. T he studies demonstrated that ERR alpha1 and ER alpha may potentially regula te the same target gene independently as well as interfere with each other' s functional activity by competition for binding and coactivator. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.