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Volume 272, Number 34, Issue of August 22, 1997 pp. 21090-21095
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The Rat Glucocorticoid Receptor Mutant K461A Differentiates between Two Different Mechanisms of Transrepression

(Received for publication, March 11, 1997, and in revised form, May 30, 1997)

Thomas Meyer ^§ , D. Barry Starr ^¶ and Jan Carlstedt-Duke

From the Departments of  Medical Nutrition and ^§ Biosciences, Novum, Karolinska Institutet, Huddinge Hospital, S-141 86 Huddinge, Sweden and ^¶ Departments of Cellular and Molecular Pharmacology, and Biochemistry and Biophysics, PIBS Biochemistry and Molecular Biology Program, University of California San Francisco, San Francisco, California 94143-0450

The glucocorticoid receptor (GR) can both activate and repress transcription of target genes by interaction with specific genomic response elements, glucocorticoid response elements (GREs). Activation of transcription is usually the result of the direct interaction between GR and the GRE, whereas GR-mediated transcription repression is either the result of the indirect action of GR, mediated by a response element as a result of protein·protein interaction or by an occlusion mechanism in which GR displaces a general or regulatory transcription factor. A specific mutation of rat GR, K461A, has previously been described to transform the indirect protein·protein interaction-dependent transrepressive effect of GR into an activating function (Starr, D. B., Matsui, W., Thomas, J. R., and Yamamoto, K. R. (1996) Genes Dev. 10, 1271-1283). In HOS D4 and COS7 cells, this mutation was shown to transform the transrepressive effect of wild-type GR, acting on reporter constructs containing the composite GRE from the proliferin gene (plfG) or the negative tethering GRE from the collagenase A promoter (colA), into an activating function. In contrast, the K461A mutation had no effect on the transrepressive effect of GR on the human osteocalcin gene in which repression apparently occurs through the binding of GR to a negative GRE that overlaps the TATA box. The transrepressive function, typically 40% of the basal level in the absence of hormone, required only the isolated DNA-binding domain of wild type or mutant GR and was independent of the nature of transactivation domain. Thus, mutation of rat GR at position 461 differentiates between transrepressive functions of GR dependent on GR·DNA interaction (repression by occlusion) and GR·protein interaction (active repression).

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