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Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a

K R Mahtani1, M Brook, J L Dean

  • 1Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London W6 8LH, United Kingdom.

Molecular and Cellular Biology
|September 5, 2001
PubMed

Insights

The p38 mitogen-activated protein kinase (MAPK) pathway regulates tumor necrosis factor alpha (TNF-alpha) mRNA stability. This pathway controls the expression and RNA-binding activity of tristetraprolin (TTP), a key protein in TNF-alpha regulation.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Immunology

Background:

  • Signal transduction pathways critically influence gene expression by altering mRNA stability.
  • The p38 MAPK pathway is known to stabilize tumor necrosis factor alpha (TNF-alpha) mRNA in myeloid cells.
  • Tristetraprolin (TTP), a zinc finger protein, is induced by lipopolysaccharide (LPS) and regulates TNF-alpha mRNA stability.

Purpose of the Study:

  • To elucidate the role of the p38 MAPK pathway in regulating TTP's interaction with TNF-alpha mRNA.
  • To investigate the mechanism by which LPS stimulation affects TTP expression and activity.
  • To establish a direct link between the p38 pathway and TTP in posttranscriptional gene regulation.

Main Methods:

  • Stimulation of RAW264.7 mouse macrophages with bacterial lipopolysaccharide (LPS).
  • Assessment of TTP binding to the TNF-alpha 3' untranslated region.
  • Analysis of p38 pathway activation, TTP protein and mRNA expression, and TTP phosphorylation.

Main Results:

  • LPS stimulation induced TTP binding to the TNF-alpha 3' untranslated region in macrophages.
  • The p38 MAPK pathway was essential for the induction of TNF-alpha RNA-binding activity and TTP expression.
  • TTP was found in differentially phosphorylated forms upon LPS stimulation, mediated by MAPKAPK2.

Conclusions:

  • The p38 MAPK pathway directly regulates TTP expression and its RNA-binding capacity.
  • MAPKAPK2 is identified as the kinase responsible for TTP phosphorylation in response to LPS.
  • This study establishes a clear connection between the p38 signaling cascade and TTP in controlling TNF-alpha mRNA stability at the posttranscriptional level.

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