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The DNA-Binding and 2 Transactivation Domains of the Rat Glucocorticoid Receptor Constitute a Nuclear Matrix-Targeting Signal

Departments of Biological Sciences (Y.T., D.B.D.), Neuroscience (D.B.D.), and Pharmacology (D.B.D.) University of Pittsburgh Pittsburgh, Pennsylvania 15260
Departments of Pathology, Medicine, Surgery, and Pharmacology and The University of Pittsburgh Cancer Institute (R.H.G., B.N.V.) University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania 15213
Departments of Pathology and Biochemistry and Molecular Biology (M.R.S.) University of Southern California Los Angeles, California 90033
Genetisches Institut der Justus-Liebig-Universität (M.E., R.R.) D35392, Giessen, Germany

Using an ATP-depletion paradigm to augment glucocorticoid receptor (GR) binding to the nuclear matrix, we have identified a minimal segment of the receptor that constitutes a nuclear matrix targeting signal (NMTS). While previous studies implicated a role for the receptor’s DNA-binding domain in nuclear matrix targeting, we show here that this domain of rat GR is necessary, but not sufficient, for matrix targeting. A minimal NMTS can be generated by linking the rat GR DNA-binding domain to either its 2 transactivation domain in its natural context, or a heterologous transactivation domain derived from the Herpes simplex virus VP16 protein. The transactivation and nuclear matrix-targeting activities of 2 are separable, as transactivation mutants were identified that either inhibited or had no apparent effect on matrix targeting of 2. A functional interaction between the NMTS of rat GR and the RNA-binding nuclear matrix protein hnRNP U was revealed in cotransfection experiments in which hnRNP U overexpression was found to interfere with the transactivation activity of GR derivatives that possess nuclear matrix-binding capacity. We have therefore ascribed a novel function to a steroid hormone transactivation domain that could be an important component of the mechanism used by steroid hormone receptors to regulate genes in their native configuration within the nucleus.

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