Functional differences between the amino-terminal domains of estrogen receptors alpha and beta

Human estrogen receptors alpha (ER alpha) and beta (ER beta) are ligand-ind ucible transcription factors that are highly homologous in their central DN A-binding and carboxyl-terminal ligand-binding domains. In contrast, there is very little conservation between ER alpha and ER beta in the amino-termi nal domain. Using different human cell lines, we show that wild-type ER bet a transcriptional activity is lower or similar to that of ER alpha, dependi ng on the cell type. Deletion of the amino-terminal domain in both ER subty pes resulted in no or a lower decrease of transcriptional activity of ER be ta compared with ER alpha, suggesting that the ER beta amino-terminal domai n contains a weaker transcriptional activation function-1. Using ER alpha a nd ER beta deletion mutants, we showed that the amino-terminal transcriptio nal activity of ER beta maps to amino acids 1-31. Interestingly, this domai n contains a six amino-acid motif (amino acids 5-10 in human ER beta) that is part of the ER alpha-activation function-1 region (amino acids 49-54 in human ER alpha) and highly conserved among all mammalian ER alpha amino-ter minal domains. Despite this similarity between the two ER subtypes, no auto nomous and ligand-independent activity of the ER beta-amino-terminal domain was observed in yeast and mammalian cells in contrast to ER alpha. This st udy provides a molecular basis for the difference in transcriptional activi ty between ER alpha and ER beta and establishes that ER beta contains a str ucturally and functionally restricted amino-terminal transcriptional activi ty.