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Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase

I Rogatsky1, S K Logan, M J Garabedian

  • 1Department of Microbiology and The Kaplan Cancer Center, New York University Medical Center, New York, NY 10016, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 16, 1998
PubMed

Insights

Mitogen-activated protein kinases JNK (c-Jun N-terminal kinase) and ERK (extracellular signal-regulated kinase) regulate the glucocorticoid receptor (GR). JNK directly phosphorylates GR at Ser-246, inhibiting its activity, while ERK acts indirectly.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Endocrinology

Background:

  • Mitogen-activated protein kinases (MAPKs) like ERK, JNK, and p38 are key regulators of cellular proliferation and inflammation.
  • The glucocorticoid receptor (GR) plays a critical role in inhibiting cell growth and inflammatory responses.
  • Cross-talk between MAPK signaling and GR activity is crucial for cellular homeostasis.

Purpose of the Study:

  • To investigate the direct and indirect mechanisms by which ERK and JNK signaling pathways modulate glucocorticoid receptor (GR) transcriptional activity.
  • To identify specific phosphorylation sites on GR targeted by these MAPKs.
  • To elucidate how MAPK-mediated GR phosphorylation impacts cellular responses.

Main Methods:

  • In vitro kinase assays to determine direct phosphorylation of GR by specific MAPKs.
  • In vivo experiments involving selective activation of ERK and JNK signaling pathways.
  • Analysis of GR-mediated transcriptional activation following MAPK stimulation.
  • Site-directed mutagenesis to examine the role of specific phosphorylation sites, such as Ser-246.

Main Results:

  • JNK and ERK, but not p38, were found to phosphorylate the glucocorticoid receptor (GR) in vitro, primarily at Ser-246.
  • Selective in vivo activation of JNK or ERK led to the inhibition of GR-mediated transcriptional activation.
  • JNK-mediated inhibition of GR activity was dependent on phosphorylation at Ser-246, indicating direct regulation.
  • ERK-mediated inhibition of GR activity occurred indirectly, suggesting involvement of other factors or pathways.

Conclusions:

  • JNK directly inhibits GR transcriptional activity through phosphorylation of Ser-246.
  • ERK indirectly inhibits GR transcriptional activity, potentially through phosphorylation of a GR cofactor.
  • These findings reveal novel mechanisms by which MAPK signaling rapidly suppresses GR-dependent gene expression when conflicting with mitogenic or inflammatory signals.

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