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Molecular and Cellular Biology, April 2000, p. 2411-2422, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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

Darko Knutti, Adesh Kaul, and Anastasia Kralli*

Division of Biochemistry, Biozentrum of the University of Basel, CH-4056 Basel, Switzerland

Received 1 November 1999/Returned for modification 12 December 1999/Accepted 3 January 2000

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 elegans proteins 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.

* Corresponding author. Mailing address: Division of Biochemistry, Biozentrum of the University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Phone: 41 61 267 2162. Fax: 41 61 267 2149. E-mail: anastasia.kralli{at}unibas.ch.

Molecular and Cellular Biology, April 2000, p. 2411-2422, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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