A Tissue-Specific Coactivator of Steroid Receptors, Identified in a Functional Genetic Screen

Abstract

Steroid receptors mediate responses to lipophilic hormones in a tissue- and ligand-specific manner. To identify nonreceptor proteins that confer specificity or regulate steroid signaling, we screened a human cDNA library in a steroid-responsive yeast strain. One of the identified cDNAs, isolated in the screen as ligand effect modulator 6, showed no homology to yeast or Caenorhabditis elegansproteins but high similarity to the recently described mouse coactivator PGC-1 and was accordingly termed hPGC-1. The hPGC-1 DNA encodes a nuclear protein that is expressed in a tissue-specific manner and carries novel motifs for transcriptional regulators. The expression of hPGC-1 in mammalian cells enhanced potently the transcriptional response to several steroids in a receptor-specific manner. hPGC-1-mediated enhancement required the receptor hormone-binding domain and was dependent on agonist ligands. Functional analysis of hPGC-1 revealed two domains that interact with steroid receptors in a hormone-dependent manner, a potent transcriptional activation function, and a putative dimerization domain. Our findings suggest a regulatory function for hPGC-1 as a tissue-specific coactivator for a subset of nuclear receptors.

ACKNOWLEDGMENTS

We thank F. Hamy, J. Iniguez-Lluhi, P. Matthias, R. Nissen, M. Parker, D. Picard, and B. Starr for sharing plasmids; Chiron and Tony Brake for the HepG2 cDNA library; R. Skoda for the human liver cDNA; Exelgyn for mifepristone (RU486); and M. Hall, J. Iniguez-Lluhi, U. Müller, D. Picard, R. Sitcheran, M. Spiess, and B. Starr for discussions and helpful comments on the manuscript.

This work was supported by the Swiss National Science Foundation (A.K.), the Basel Chemical Industry (D.K.), and the Max Cloëtta Foundation (A.K.).