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Domains of the Glucocorticoid Receptor Involved in Specific and Nonspecific Deoxyribonucleic Acid Binding, Hormone Activation, and Transcriptional Enhancement

Mark Danielsen^*, Jeffrey P. Northrop, Jacqueline Jonklaas and Gordon M. Ringold

Department of Pharmacology, Stanford University School of Medicine, Stanford University Medical Center Stanford, California 94305-5332

Address requests for reprints to: Dr. Mark Danielsen, Department of Pharmacology, Stanford University School of Medicine, Stanford University Medical Center, Stanford, California 94305-5332.

Abstract

We have analyzed the domain structure of the mouse glucocorticoid receptor by expression of in vitro mutated receptor in COS-7 cells. The receptor consists of a core domain rich in Cys, Lys, and Arg amino acids which can bind specific DNA sequences (glucocorticoid response elements) and activate transcription. The activity of this centrally located domain is modulated by the activity of the other two domains. The N-terminal domain of the receptor plays a role in decreasing nonspecific DNA binding and may therefore improve the ability of the protein to discriminate between specific and nonspecific DNA binding sites. This activity maps to a small, highly acidic region of the N-terminal domain. The C-terminal domain of the receptor contains the glucocorticoid binding site and in addition represses the transcriptional activity of the receptor in the absence of hormone. Hormone binding relieves the repression allowing transcription activation. The Cterminal domain contains a short sequence conserved among steroid receptors; its deletion yields a receptor that activates transcription in the absence of hormone.

FOOTNOTES

This work was supported in part by NIH Grant GM-25821 (to G.M.R.).

^* Leukemia Society of America Special Fellow.

Present address: Syntex Research, 3401 Hillview Avenue, Palo Alto, CA 94304.

Received for publication August 3, 1987. Accepted for publication September 8, 1987.

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