Truncated estrogen receptor product-1 suppresses estrogen receptor transactivation by dimerization with estrogen receptors alpha and beta.
The estrogen receptor (ER) is a ligand-activated transcription factor that acts as a homodimer. Truncated estrogen receptor product-1 (TERP-1) is a pituitary-specific, estrogen-induced, isoform of rat ERalpha that is transcribed from a unique start site and contains only the C-terminal region of the full-length receptor. TERP-1 does not affect transcription directly but suppresses ligand-activated ERalpha and ERbeta activity. Because TERP-1 contains a dimerization domain and part of the coactivator binding pocket, we hypothesized that it modulates ER function by direct interactions with full-length ER or the steroid receptor coactivator, SRC-1. Localization studies demonstrate that TERP-1 is present in the cytoplasm and nucleus of transfected cells and colocalizes with nuclear ER. Protein binding studies show that TERP-1 forms heterodimers with both ERalpha and ERbeta and inhibits ERalpha binding to its cognate DNA response element. TERP-1 also binds SRC-1, and increasing levels of SRC-1 decrease the TERP-1-ERalpha interactions, in agreement with the rescue of TERP-1-suppressed ERalpha transcriptional activity by SRC-1. Mutational analysis of TERP-1 and ERalpha in the activation helix and the AF-2 dimerization helix indicates that TERP-1 acts predominantly through dimerization with ERalpha. Therefore, TERP-1 suppression of ER transcription occurs primarily by formation of inactive heterodimers and secondarily by competition for coactivators.
Resnick
E M
EM
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22903, USA.
Schreihofer
D A
DA
Periasamy
A
A
Shupnik
M A
MA
D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002467:Cell Nucleus / Q000737:chemistry; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000502:physiology; D019281:Dimerization; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051381:Rats; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology; D012097:Repressor Proteins; D020218:Response Elements; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C539967:Nr0b1 protein, rat; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; C118565:TERP-1; D014157:Transcription Factors