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Translating Ribosome Affinity Purification (TRAP) for RNA Isolation from Endothelial Cells In Vivo
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Published on: May 25, 2019

Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA

Khadija Essafi-Benkhadir1, Cercina Onesto, Emmanuelle Stebe

  • 1Unité Mixte de Recherche Centre National de la Recherche Scientifique 6543, University of Nice-Sophia Antipolis, Equipe Labellisée Ligue Nationale Contre le Cancer, 06189 Nice Cedex, France.

Molecular Biology of the Cell
|September 15, 2007
PubMed

Insights

Tristetraprolin (TTP) degrades vascular endothelial growth factor (VEGF) mRNA. ERK activation reduces TTP’s effect, increasing VEGF and promoting tumor angiogenesis, suggesting TTP as an anti-cancer target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Vascular endothelial growth factor (VEGF) drives angiogenesis in both normal and pathological conditions.
  • Tumors often exhibit constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and VEGF overexpression.
  • VEGF mRNA stability is a critical factor in regulating VEGF expression.

Purpose of the Study:

  • To investigate the link between ERK pathway activation, VEGF mRNA stability, and tumor angiogenesis.
  • To elucidate the role of tristetraprolin (TTP) in regulating VEGF mRNA levels.
  • To explore the potential of TTP as an anti-angiogenic and anti-tumor agent.

Main Methods:

  • Studied the interaction of TTP with the 3'-untranslated region of VEGF mRNA.
  • Assessed the effect of ERK activation on TTP mRNA accumulation and VEGF mRNA stability.
  • Evaluated TTP's impact on RasVal12-induced VEGF expression and tumor vascularization in nude mouse models.

Main Results:

  • TTP binds to VEGF mRNA and promotes its degradation, maintaining normal VEGF levels.
  • ERK activation leads to increased TTP mRNA but paradoxically reduces TTP's VEGF mRNA destabilizing activity.
  • This reduction in TTP's function by ERK results in elevated VEGF expression, promoting angiogenesis.
  • TTP administration inhibited RasVal12-driven VEGF expression and reduced tumor vascularization in vivo.

Conclusions:

  • ERK activation disrupts TTP-mediated VEGF mRNA decay, contributing to tumor angiogenesis.
  • TTP acts as a negative regulator of VEGF expression and tumor vascularization.
  • TTP holds promise as a novel anti-angiogenic and anti-tumor therapeutic agent.
  • Assessing TTP and ERK status may help predict the angiogenic potential of human tumors.

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