A Nuclear Action of the Eukaryotic Cochaperone RAP46 in Downregulation of Glucocorticoid Receptor Activity

Correspondence to: Andrew C.B. Cato, Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, D-76021 Karlsruhe, Germany. Tel:49-7247-822146 Fax:49-7247-823354 E-mail: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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Malkesman, O., Austin, D. R., Chen, G., Manji, H. K. (2009). Reverse translational strategies for developing animal models of bipolar disorder. DMM 2: 238-245 [Abstract] [Full Text]  
• Schmidt, U., Holsboer, F., Rein, T. (2008). Role of the hsp70 cochaperone BAG1 in glucocorticoid receptor function and stress-related diseases. Proc. Natl. Acad. Sci. USA 105: E101-E101 [Full Text]  
• Maeng, S., Hunsberger, J. G., Pearson, B., Yuan, P., Wang, Y., Wei, Y., McCammon, J., Schloesser, R. J., Zhou, R., Du, J., Chen, G., McEwen, B., Reed, J. C., Manji, H. K. (2008). BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments. Proc. Natl. Acad. Sci. USA 105: 8766-8771 [Abstract] [Full Text]  
• Zhou, R., Gray, N. A., Yuan, P., Li, X., Chen, J., Chen, G., Damschroder-Williams, P., Du, J., Zhang, L., Manji, H. K. (2005). The Anti-Apoptotic, Glucocorticoid Receptor Cochaperone Protein BAG-1 Is a Long-Term Target for the Actions of Mood Stabilizers. J. Neurosci. 25: 4493-4502 [Abstract] [Full Text]  
• Shatkina, L., Mink, S., Rogatsch, H., Klocker, H., Langer, G., Nestl, A., Cato, A. C. B. (2003). The Cochaperone Bag-1L Enhances Androgen Receptor Action via Interaction with the NH2-Terminal Region of the Receptor. Mol. Cell. Biol. 23: 7189-7197 [Abstract] [Full Text]  
• Niyaz, Y., Frenz, I., Petersen, G., Gehring, U. (2003). Transcriptional stimulation by the DNA binding protein Hap46/BAG-1M involves hsp70/hsc70 molecular chaperones. Nucleic Acids Res 31: 2209-2216 [Abstract] [Full Text]  
• Schmidt, U., Wochnik, G. M., Rosenhagen, M. C., Young, J. C., Hartl, F. U., Holsboer, F., Rein, T. (2003). Essential Role of the Unusual DNA-binding Motif of BAG-1 for Inhibition of the Glucocorticoid Receptor. J. Biol. Chem. 278: 4926-4931 [Abstract] [Full Text]  
• Nollen, E. A. A., Morimoto, R. I. (2002). Chaperoning signaling pathways: molecular chaperones as stress-sensing `heat shock' proteins. J. Cell Sci. 115: 2809-2816 [Abstract] [Full Text]  
• Kudoh, M., Knee, D. A., Takayama, S., Reed, J. C. (2002). Bag1 Proteins Regulate Growth and Survival of ZR-75-1 Human Breast Cancer Cells. Cancer Res. 62: 1904-1909 [Abstract] [Full Text]  
• Cheung, J., Smith, D. F. (2000). Molecular Chaperone Interactions with Steroid Receptors: an Update. Mol. Endocrinol. 14: 939-946 [Full Text]  
• Luders, J., Demand, J., Papp, O., Hohfeld, J. (2000). Distinct Isoforms of the Cofactor BAG-1 Differentially Affect Hsc70 Chaperone Function. J. Biol. Chem. 275: 14817-14823 [Abstract] [Full Text]  
• Petersen, G., Hahn, C., Gehring, U. (2001). Dissection of the ATP-binding Domain of the Chaperone hsc70 for Interaction with the Cofactor Hap46. J. Biol. Chem. 276: 10178-10184 [Abstract] [Full Text]  
• Rao, J., Lee, P., Benzeno, S., Cardozo, C., Albertus, J., Robins, D. M., Caplan, A. J. (2001). Functional Interaction of Human Cdc37 with the Androgen Receptor but Not with the Glucocorticoid Receptor. J. Biol. Chem. 276: 5814-5820 [Abstract] [Full Text]  
• Wang, Q., Lu, J., Yong, E. L. (2001). Ligand- and Coactivator-mediated Transactivation Function (AF2) of the Androgen Receptor Ligand-binding Domain Is Inhibited by the Cognate Hinge Region. J. Biol. Chem. 276: 7493-7499 [Abstract] [Full Text]  
• Lin, J., Hutchinson, L., Gaston, S. M., Raab, G., Freeman, M. R. (2001). BAG-1 Is a Novel Cytoplasmic Binding Partner of the Membrane Form of Heparin-binding EGF-like Growth Factor. A UNIQUE ROLE FOR proHB-EGF IN CELL SURVIVAL REGULATION. J. Biol. Chem. 276: 30127-30132 [Abstract] [Full Text]  
• Knee, D. A., Froesch, B. A., Nuber, U., Takayama, S., Reed, J. C. (2001). Structure-Function Analysis of Bag1 Proteins. EFFECTS ON ANDROGEN RECEPTOR TRANSCRIPTIONAL ACTIVITY. J. Biol. Chem. 276: 12718-12724 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents