Estrogen-related receptor alpha 1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells.
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.
Kraus
Richard J
RJ
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Ariazi
Eric A
EA
Farrell
Michael L
ML
Mertz
Janet E
JE
D001483:Base Sequence; D001943:Breast Neoplasms; D016384:Consensus Sequence; D017931:DNA Primers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000097983:ERRalpha Estrogen-Related Receptor
D017931:DNA Primers; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor