被撤回的出版物: An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERR gamma (Retracted article. See vol. 47, pg. 1604, 2019)

The estrogen receptor-related receptor gamma (ERR gamma/ERR3/NR3B3) is a member of the nuclear receptor superfamily that activates transcription in the absence of ligand. However, the detailed mechanism of gene regulation by ERR gamma is not fully understood. In this study we have found that the orphan nuclear receptor ERR gamma activates the DAX-1 promoter, which, in turn, represses transactivation by ERR gamma. Serial deletions of mouse DAX-1 (mDAX-1) gene promoter have revealed that the region responding to ERR gamma is located between -129 and -121 bp and -334 and -326 bp. Gel shift assays and chromatin immunoprecipitation (ChIP) assays demonstrated that ERR gamma binds directly to the mDAX-1 promoter. Site-directed mutagenesis results demonstrated that ERRE1 (-129 to -121 bp) is more important than ERRE2 (-334 to -326 bp) which is not conserved in the human DAX-1 promoter. In addition, adenovirus-mediated overexpression of ERR gamma induced DAX-1 gene expression in MCF-7 breast cancer cells that co-expressed ERR gamma and DAX-1. Moreover, yeast two-hybrid and glutathione S-transferase (GST)-pull down assays demonstrated that DAX-1 physically interacted with ERR gamma and inhibited ERR gamma transactivation, and that this interaction was dependent on the AF-2 domain of ERR gamma. In addition, in vitro competition assays showed that DAX-1 inhibited PGC-1 alpha mediated ERR gamma transactivation, via competition between these two factors for the AF-2 binding domain. We thus propose a novel autoregulatory loop that controls DAX-1 gene expression by ERR gamma.