Regulation of Glucocorticoid Receptor Activity by 14–3-3-Dependent Intracellular Relocalization of the Corepressor RIP140

Abstract

Proteins belonging to the 14--3-3 family interact with various regulatory proteins involved in cellular signaling, cell cycle regulation, or apoptosis. 14--3-3 proteins have been suggested to act by regulating the cytoplasmic/nuclear localization of their target proteins or by acting as molecular scaffolds or chaperones. We have previously shown that overexpression of 14--3-3 enhances the transcriptional activity of the glucocorticoid receptor (GR), which is a member of the nuclear receptor family. In this study, we show that 14--3-3 interacts with the nuclear receptor corepressor RIP140. In transfection assays, RIP140 antagonizes 14--3-3- enhanced GR transactivation. Using colocalization studies we demonstrate that 14--3-3 can export RIP140 out of the nucleus and, interestingly, can also change its intranuclear localization. Moreover, we also observed that 14--3-3 can bind various other nuclear receptors and cofactors. In summary, our findings suggest that 14--3-3-mediated intracellular relocalization of the GR corepressor RIP140 might be a novel mechanism to enhance glucocorticoid responsiveness of target genes. They furthermore indicate a more general role for 14--3-3 protein by influencing the nuclear availability of nuclear receptor-associated cofactors.

Subcellular Localization and Mechanisms of Nucleocytoplasmic Trafficking of Steroid Receptor Coactivator-1

“…Similarly, nucleocytoplasmic trafficking of coregulators may constitute a supplementary step to control transcriptional activity of steroid receptors in response to changing physiological conditions (21,24). A rapid export of the coactivator can terminate hormone action if the receptor export is slow, as we have observed in the case of PR (45).…”

Activity and subcellular compartmentalization of peroxisome proliferator-activated receptor α are altered by the centrosome-associated protein CAP350

“…Nuclear compartmentalization plays an important role in gene regulation, and many transcription factors, including steroid and nuclear hormone receptors such as the glucocorticoid, estrogen, thyroid and retinoic acid receptors, and nuclear receptor coregulatory molecules such as GRIP-1, SMRT, SRC-1, and RIP140, have been shown to accumulate in discrete foci distributed throughout the nucleoplasm (Carmo-Fornesca, 2002;Doucas, 2002;Hendzel et al, 2001;Zilliacus et al, 2001;Tazawa et al, 2003;van Steensel et al, 1995). The identity, composition and function of these foci remain to be elucidated.…”

Proteomic identification of 14-3-3 sigma as a common component of the androgen receptor and the epidermal growth factor receptor signaling pathways of the human prostate epithelial cell line M12

“…There are seven isoforms of 14-3-3 expressed in humans, which appear to exert different effects in cells depending on cell type-specific isoform expression, subcellular location, and differential target specificity (Tzivion and Avruch, 2002). The 14-3-3 sigma protein is the predominant isoform expressed in epithelial cells (Yaffe, 2002) and can bind to several steroid hormone receptors, including the AR (Zilliacus et al, 2001). Cotransfection of a different 14-3-3 isoform, 14-3-3-eta, enhances AR dependent stimulation of a luciferase reporter construct, but the mechanism remains unknown (Haendler et al, 2001).…”