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Molecular and Cellular Biology, January 2002, p. 357-369, Vol. 22, No. 1
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.1.357-369.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of a Tissue-Specific Coactivator, GT198, That Interacts with the DNA-Binding Domains of Nuclear Receptors

Lan Ko,1,2* Guemalli R. Cardona,1 Alexandra Henrion-Caude,3 and William W. Chin1

Department of Gene Regulation, Bone and Inflammation Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285,1 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215,2 INSERM U515, Hôpital d’Enfants Armand Trousseau, Paris, France3

Received 22 March 2001/ Returned for modification 7 June 2001/ Accepted 3 October 2001

Gene activation mediated by nuclear receptors is regulated in a tissue-specific manner and requires interactions between nuclear receptors and their cofactors. Here, we identified and characterized a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. GT198 was originally described as a genomic transcript that mapped to the human breast cancer susceptibility locus 17q12-q21 with unknown function. We show that GT198 exhibits a tissue-specific expression pattern in which its mRNA is elevated in testis, spleen, thymus, pituitary cells, and several cancer cell lines. GT198 is a 217-amino-acid nuclear protein that contains a leucine zipper required for its dimerization. In vitro binding and yeast two-hybrid assays indicated that GT198 interacted with nuclear receptors through their DNA-binding domains. GT198 potently stimulated transcription mediated by estrogen receptor {alpha} and ß, thyroid hormone receptor ß1, androgen receptor, glucocorticoid receptor, and progesterone receptor. However, the action of GT198 was distinguishable from that of the ligand-binding domain-interacting nuclear receptor coactivators, such as TRBP, CBP, and SRC-1, with respect to basal activation and hormone sensitivity. Furthermore, protein kinase A, protein kinase C, and mitogen-activated protein kinase can phosphorylate GT198 in vitro, and cotransfection of these kinases regulated the transcriptional activity of GT198. These data suggest that GT198 is a tissue-specific, kinase-regulated nuclear receptor coactivator that interacts with the DNA-binding domains of nuclear receptors.

* Corresponding author. Mailing address: Eli Lilly and Company, Lilly Corporate Center, Building 98/C, Drop Code 0434, Indianapolis, IN 46285. Phone: (317) 433-5237. Fax: (317) 276-1414. E-mail: kol{at}lilly.com.

Molecular and Cellular Biology, January 2002, p. 357-369, Vol. 22, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.1.357-369.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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