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The role of glucocorticoid receptor phosphorylation in Mcl-1 and NOXA gene expression

James T Lynch1, Ramkumar Rajendran, Georgia Xenaki

  • 1School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Manchester, UK.

Molecular Cancer
|February 17, 2010
PubMed
Abstract

Insights

Glucocorticoid receptor (GR) phosphorylation patterns influence leukemia cell fate and response to glucocorticoids (GCs). Differential GR phosphorylation and isoform expression determine cell-specific apoptosis, impacting GC therapy effectiveness.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylation of glucocorticoid receptor (GR) have opposing effects on its activity.
  • GR phosphorylation at serine 226 (by MAPK) and serine 211 (by various kinases) are key modifications.
  • Investigated the role of GR posttranslational modifications in determining cellular fate and glucocorticoid-induced apoptosis in human lymphoblastic leukemia cells.

Purpose of the Study:

  • To investigate the cell type specificity of glucocorticoid (GC)-mediated apoptosis.
  • To determine if alternative GR phosphorylation, influenced by UV signaling, dictates this specificity.
  • To explore the link between GR posttranslational modifications and cellular fate in leukemia.

Main Methods:

  • Identified Glucocorticoid Response Elements (GREs) in NOXA and Mcl-1 promoters.
  • Analyzed differential gene regulation by GCs and JNK pathway in CEM-C7-14, CEM-C1-15, and A549 cells.
  • Characterized GR phosphorylation sites (S211, S226) and identified GR isoforms using specific antibodies.

Main Results:

  • NOXA and Mcl-1 are direct GR transcriptional targets, differentially regulated by GCs and JNK pathway.
  • S211 phosphorylation was dominant in CEM-C7-14 cells, while S226 phosphorylation prevailed in CEM-C1-15 cells.
  • Multiple GR isoforms were identified, with cell line-specific patterns observed.

Conclusions:

  • GR phosphorylation kinetics, site specificity, and isoform variability differ across leukemia cell lines (CEM-C7-14, CEM-C1-15, A549).
  • GC-induced apoptosis is determined by the variable balance of NOXA and Mcl-1 gene expression, mediated by alternatively phosphorylated GR.
  • The balance of MAPK/CDK pathways controlling GR phosphorylation patterns provides a molecular basis for improving GC-based leukemia therapies.

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