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Modulation of glucocorticoid receptor transcriptional activation, phosphorylation, and growth inhibition by p27Kip1

Zhen Wang1, Michael J Garabedian

  • 1Department of Microbiology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.

The Journal of Biological Chemistry
|October 10, 2003
PubMed

Insights

The cyclin-dependent kinase inhibitor p27 (p27Kip1) plays a role in glucocorticoid receptor (GR) activity. Loss of p27 enhances GR signaling and reduces sensitivity to glucocorticoid-induced growth inhibition.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • p27Kip1 is a cyclin-dependent kinase inhibitor often inactivated in human cancers.
  • Glucocorticoids, via the glucocorticoid receptor (GR), are used in cancer treatment and exhibit growth-inhibitory effects.
  • The interplay between GR activity and p27 status remains largely unexplored.

Purpose of the Study:

  • To investigate the relationship between glucocorticoid receptor (GR) activity and p27Kip1 status.
  • To examine GR-dependent transcriptional activation, receptor phosphorylation, and growth inhibition in p27-deficient cells.

Main Methods:

  • Utilized p27-deficient (p27-/-) murine embryonic fibroblasts (MEFs).
  • Assessed GR transcriptional activation and receptor phosphorylation.
  • Evaluated glucocorticoid-dependent growth inhibition.

Main Results:

  • p27-/- MEFs exhibited elevated GR transcriptional enhancement and GR phosphorylation at key sites compared to controls.
  • Increased GR activity was linked to the GR N-terminus and potentiated by DRIP150.
  • p27-/- MEFs showed partial resistance to the growth-inhibitory effects of glucocorticoids.

Conclusions:

  • p27Kip1 is a significant regulator of GR-mediated transcriptional activity.
  • p27Kip1 influences cellular responses to glucocorticoids, impacting growth inhibition.
  • These findings highlight p27's role in the GR signaling pathway relevant to cancer therapy.

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