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Post-transcriptional regulation of MEK-1 by polyamines through the RNA-binding protein HuR modulating intestinal

Peng-Yuan Wang1, Jaladanki N Rao, Tongtong Zou

  • 1Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

The Biochemical Journal
|December 17, 2009
PubMed

Insights

Cellular polyamines regulate MEK-1 expression post-transcriptionally via the HuR protein in intestinal epithelial cells. Polyamines destabilize MEK-1 mRNA, impacting cell apoptosis resistance.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Signal Transduction

Background:

  • Mitogen-activated protein kinase kinase-1 (MEK-1) is crucial for cellular functions.
  • Polyamines are essential for cell growth and differentiation.
  • The RNA-binding protein HuR (Hu-antigen R) plays a role in post-transcriptional gene regulation.

Purpose of the Study:

  • To investigate the role of cellular polyamines in regulating MEK-1 expression.
  • To elucidate the mechanism by which polyamines affect MEK-1 mRNA stability and translation.
  • To determine the involvement of HuR in polyamine-mediated MEK-1 regulation and its impact on apoptosis in intestinal epithelial cells (IECs).

Main Methods:

  • Manipulation of cellular polyamine levels by inhibiting or overexpressing ornithine decarboxylase (ODC).
  • Assessment of MEK-1 mRNA stability and translation efficiency.
  • Analysis of the interaction between HuR and the 3'-untranslated region of MEK-1 mRNA.
  • Gene silencing techniques (siRNA) to inhibit MEK-1 and HuR expression.
  • Apoptosis assays to evaluate cell survival.

Main Results:

  • Decreased polyamine levels stabilized MEK-1 mRNA and enhanced its translation by increasing HuR binding.
  • Increased polyamine levels destabilized MEK-1 mRNA and repressed translation by reducing HuR-MEK-1 complex formation.
  • Neither polyamine level alteration affected MEK-1 gene transcription.
  • HuR silencing led to MEK-1 mRNA instability and inhibited translation, preventing increased MEK-1 levels in polyamine-deficient cells.
  • HuR overexpression increased MEK-1 mRNA stability and translation.
  • Inhibition of MEK-1 or HuR expression abrogated the increased resistance to apoptosis in polyamine-deficient cells.

Conclusions:

  • Cellular polyamines destabilize MEK-1 mRNA and repress its translation by modulating the HuR-MEK-1 mRNA interaction.
  • MEK-1 is a critical mediator of the HuR-dependent anti-apoptotic pathway in intestinal epithelial cells.

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