Estrogen receptor α and estrogen receptor-related receptor α1 compete for binding and coactivator

Abstract The human estrogen receptor (ERα) and the human estrogen receptor-related receptor (ERRα1, NR3B1a) are members of the steroid/thyroid hormone receptor superfamily. We previously cloned an isoform of ERRα1 cDNA and demonstrated that ERRα1 binds to the human lactoferrin gene promoter and enhances estrogen responsiveness during transient transfection experiments. In this study, we show that ERRα1 and ERα may interfere in each other's transcriptional activity by competition for binding and coactivator. A VP16-ERRα1 chimera was constructed and transiently transfected into human endometrial carcinoma HEC-1B cells. This chimera activated reporter constructs containing the human lactoferrin gene estrogen response element (ERE) and the synthetic palindromic 3X-ERE, suggesting that ERRα1 binds to these EREs. Therefore, ERRα1 can compete with ERα for binding to the same EREs. ERRα1 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 function of ERRα1 was mapped to the conserved AF2 region in the C-terminus by deletion analysis. The transactivation activity of ERRα1 can be enhanced by coactivator (SRC-1a) and suppressed by ERα in the presence of estrogen, suggesting that SRC-1a is required by both receptors for their activity. The repression of ERRα1 activation function by estrogen bound ERα, however, could not be reversed by increasing concentration of SRC-1a in the cells. This finding is consistent with the squelching phenomenon that exists between ERα and other steroid receptor family members. The studies demonstrated that ERRα1 and ERα may potentially regulate the same target gene independently as well as interfere with each other's functional activity by competition for binding and coactivator.

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