ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator

Abstract

We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ERα-interacting proteins using the ERα 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 ERα, ERAP140 also binds ERβ, TRβ, PPARγ, and RARα. ERAP140 interacts with ERα via a noncanonical interaction motif. The ERα-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ERα 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 ERα to the promoter region of endogenous ERα target genes. Furthermore, the E₂-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.

We thank Urs Berger for performing the in situ hybridization analyses, the Dana-Farber Molecular Biology Core Facility for DNA sequencing, William Sellers for plasmids, James DiRenzo and Yongfeng Shang for helpful discussions, and Clare Galtrey for reading the manuscript and for insightful suggestions.

This work was supported by NIH grant RO1-CA57374 and Academic Award DAMD 17-99-1-9161 from the U.S. Department of Defense Breast Cancer Research Program to M.B. and a fellowship from the Massachusetts Department of Public Health Breast Cancer Research Program to W.S.