ERAP140, a conserved tissue-specific nuclear receptor coactivator.
We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ER alpha-interacting proteins using the ER alpha ligand binding domain as a probe. The ERAP140 protein shares no sequence and has little structural homology with other nuclear receptor cofactors. However, homologues of ERAP140 have been identified in mouse, Drosophila, and Caenorhabditis elegans. The expression of ERAP140 is cell and tissue type specific and is most abundant in the brain, where its expression is restricted to neurons. In addition to interacting with ER alpha, ERAP140 also binds ER beta, TR beta, PPAR gamma, and RAR alpha. ERAP140 interacts with ER alpha via a noncanonical interaction motif. The ER alpha-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ER alpha on a surface similar to that of other coactivators. ERAP140 can enhance the transcriptional activities of nuclear receptors with which it interacts. In vivo, ERAP140 is recruited by estrogen-bound ER alpha to the promoter region of endogenous ER alpha target genes. Furthermore, the E(2)-induced recruitment of ERAP140 to the promoter follows a cyclic pattern similar to that of other coactivators. Our results suggest that ERAP140 represents a distinct class of nuclear receptor coactivators that mediates receptor signaling in specific target tissues.
Shao
Wenlin
W
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Halachmi
Shlomit
S
Brown
Myles
M
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D047628:Estrogen Receptor alpha; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C455500:NCOA7 protein, human; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D011506:Proteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors