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© The Rockefeller University Press, 0021-9525/1999//929 $5.00
The Journal of Cell Biology, Volume 146, Number 5, , 1999 929-940

A Nuclear Action of the Eukaryotic Cochaperone Rap46 in Downregulation of Glucocorticoid Receptor Activity

^a Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, D-76021 Karlsruhe, Germany.49-7247-82335449-7247-822146

andrew.cato{at}igen.fzk.de

RAP46 is a eukaryotic cochaperone that associates with several proteins, including the heat shock protein hsp70/hsc70 and the glucocorticoid receptor (GR). Here we show a downregulation of GR-mediated transactivation by RAP46 via a mechanism independent of a cytoplasmic action of this cochaperone. We demonstrate a specific cytoplasmic–nuclear recruitment of RAP46 by the liganded GR that results in inhibition of the transactivation function of the receptor. A repeated sequence motif [EEX₄]₈ at the NH₂ terminus of RAP46 or BAG-1L, a larger isoform of RAP46, is responsible for this downregulation of GR activity. BAG-1, a shorter isoform with only a duplication of the [EEX₄] sequence, does not inhibit GR activity. The [EEX₄]₈ motif, when linked to an otherwise unrelated protein, abrogated the inhibitory action of endogenous RAP46 on GR-mediated transactivation. The nuclear effects of RAP46 and BAG-1L are specific since GR-mediated inhibition of AP-1 activity was not affected. These studies identify the [EEX₄]₈ sequence as a signature motif for inhibition of GR-mediated transactivation and demonstrate a specific nuclear action of a eukaryotic cochaperone in the regulation of GR activity.

Key Words: glucocorticoid receptor • mineralocorticoid receptor • transactivation • BAG-1 isoforms • cochaperone

© 1999 The Rockefeller University Press

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