The F domain of estrogen receptor ? is involved in species-specific, tamoxifen-mediated transactivation.

ABSTRACT: Estrogen receptor ? (ER?) is a major transducer of estrogen-mediated physiological signals. ER? is a member of the nuclear receptor superfamily, which encompasses ligand-dependent transcription factors. The C terminus of nuclear receptors, termed the F domain, is the least homologous region among the members of this family. The ER? F domain possesses 45 amino acids; however, its function remains unclear. We noticed that the homology of the F domains between mouse and human ER?s is remarkably lower (75.6% similarity) than that between the entire proteins (94.7% similarity). To assess the functionality of the ER? F domains, here we generated chimeric ER? expression constructs with mouse-human-exchanged F domains. Using cell-based in vitro assays, we analyzed the transcriptional coactivator interaction and ligand-binding domain dimerization activities of these mouse-human F domain-swapped ER?s. We found that the transcriptional activity of the mouse WT ER? is more potent than that of the human WT ER? in the human hepatoma cell line HepG2. 4-Hydroxytamoxifen (4OHT)-mediated transcriptional activity of mouse-human F domain-swapped ER?s was the inverse of the WT ER? activities but not estradiol-mediated transcriptional activities. Further experiments with constructs containing deletion or point mutations of a predicted ?-strand region within the F domain suggested that this region governs the species-specific 4OHT-mediated transcriptional activity of ER?. We conclude that the ER? F domain has a species-specific function in 4OHT-mediated receptor transactivation and that mouse-human F domain-swapped ER? mutants enable key insights into ER? F domain structure and function.

SUBMITTER: Arao Y 

PROVIDER: S-EPMC5986198 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature