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The glucocorticoid receptor represses cyclin D1 by targeting the Tcf-beta-catenin complex

Sachiko Takayama1, Inez Rogatsky, Leslie E Schwarcz

  • 1Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, OR 97403-1229, USA.

The Journal of Biological Chemistry
|April 29, 2006
PubMed

Insights

Glucocorticoids (GCs) repress cyclin D1 via the Wnt pathway effector beta-catenin in growth-arrested cells. This direct link suggests new tissue-selective GC therapies targeting cell proliferation.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Biology

Background:

  • Glucocorticoids (GCs) regulate cell proliferation, crucial for their therapeutic applications.
  • The canonical Wnt pathway promotes proliferation in cancers and tissues, representing a potential target for GCs.
  • Existing links between GC and Wnt signaling are indirect, necessitating further investigation.

Purpose of the Study:

  • To identify Wnt target genes differentially regulated by GCs in cells with varying proliferation responses.
  • To elucidate the direct molecular mechanisms linking glucocorticoid receptor (GR) and Wnt signaling.
  • To explore the therapeutic potential of targeting the Wnt pathway with GCs.

Main Methods:

  • Screening of Wnt target genes for differential GC response in specific cell lines.
  • Investigating the interaction between GR and beta-catenin using in vitro binding assays.
  • Utilizing RNA interference to down-regulate beta-catenin and assess its impact on gene expression and cell proliferation.

Main Results:

  • Identified c-myc, c-jun, and cyclin D1 as Wnt target genes differentially affected by GCs.
  • Demonstrated that GR represses cyclin D1 expression via Tcf-beta-catenin in GC-growth-arrested U2OS/GR cells.
  • Showed direct binding between GR and beta-catenin in vitro.
  • Found that beta-catenin down-regulation affected cyclin D1 but not c-myc or c-jun expression, with no significant impact on U2OS/GR cell proliferation.

Conclusions:

  • Established a direct molecular link between GC and Wnt signaling pathways through GR and beta-catenin.
  • While beta-catenin and cyclin D1 are not essential for proliferation in this specific cell model, their repression by GR is significant.
  • The repression of Tcf-beta-catenin activity by GR offers potential for developing tissue-selective GC therapies targeting cell proliferation and differentiation.

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