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

Mol Endocrinol. 2001 Apr;15(4):501-11. doi: 10.1210/mend.15.4.0624.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins
  • Adaptor Proteins, Signal Transducing
  • Animals
  • COS Cells
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Interacting Protein 1
  • Phosphorylation
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Retinoid X Receptors
  • Subcellular Fractions
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism*

Substances

  • 14-3-3 Proteins
  • Adaptor Proteins, Signal Transducing
  • Nuclear Proteins
  • Nuclear Receptor Interacting Protein 1
  • Receptors, Androgen
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Glucocorticoid
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Retinoid X Receptors
  • Transcription Factors
  • Tyrosine 3-Monooxygenase