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Molecular and Cellular Biology, May 2002, p. 3358-3372, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3358-3372.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator

Wenlin Shao, Shlomit Halachmi, and Myles Brown*

Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

Received 7 November 2001/ Returned for modification 10 January 2002/ Accepted 7 February 2002

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 ERß, TRß, 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 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.

* Corresponding author. Mailing address: Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3948. Fax: (617) 632-5417. E-mail: myles_brown{at}dfci.harvard.edu.

Molecular and Cellular Biology, May 2002, p. 3358-3372, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3358-3372.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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