Abstract
The estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily. We show that the major isoform of the human ERRalpha gene, ERRalpha1, can sequence-specifically bind a consensus palindromic estrogen response element (ERE) and directly compete with estrogen receptor alpha (ERalpha) for binding. ERRalpha1 activates or represses ERE-regulated transcription in a cell type-dependent manner, repressing in ER-positive MCF-7 cells while activating in ER-negative HeLa cells. Thus, ERRalpha1 can function both as a modulator of estrogen responsiveness and as an estrogen-independent activator. Repression likely occurs in the absence of exogenous ligand since charcoal treatment of the serum had no effect on silencing activity. Mutational analysis revealed that repression is not simply the result of competition between ERalpha and ERRalpha1 for binding to the DNA. Rather, it also requires the presence of sequences within the carboxyl-terminal E/F domain of ERRalpha1. Thus, ERRalpha1 can function as either an active repressor or a constitutive activator of ERE-dependent transcription. We hypothesize that ERRalpha1 can play a critical role in the etiology of some breast cancers, thereby providing a novel therapeutic target in their treatment.
Highlights
Mones), some, termed orphan receptors, share significant sequence similarity in their LBDs with their ligand binding family members but lack as-yet known naturally occurring ligands [7,8,9,10]
We examined here the transcriptional properties of estrogen-related receptor ␣ (ERR␣)1 when it acts via binding an estrogen response element (ERE)
We showed that ERR␣1 directly competes with ER␣ for binding to a consensus palindromic ERE (Fig. 2) and down-modulates the transcriptional response to estrogen in an ERE-dependent manner in MCF-7 cells (Figs. 3 and 4)
Summary
Mones), some, termed orphan receptors, share significant sequence similarity in their LBDs with their ligand binding family members but lack as-yet known naturally occurring ligands [7,8,9,10]. A third member of the ERR family, ERR␥ (NR3B3), has been identified [13,14,15] These three ERRs are closely related by sequence similarity but encoded by different genes. The ERRs differ somewhat from the ERs in their binding site specificities They recognize estrogen response elements (EREs) [11, 25,26,27,28,29]; ERR␣1 binds with even higher affinity to the consensus steroidogenic factor-1 response element-extended half-site sequence 5Ј-TCAAGGTCA-3Ј [11, 27, 26]. The ERR family members have been shown to function in numerous cell types as transcriptional activators of promoters containing EREs, steroidogenic factor-1 response elements, and ER response elements (16 –31). We found that ERR␣1 repressed rather than activated transcription in ER-negative CV-1 cells when it binds sites within the late
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