Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells

Christine Bourcier, Paola Griseri, Renaud Grépin, Corinne Bertolotto, Nathalie Mazure, Gilles Pagès

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Most melanoma cells are characterized by the V600E mutation in B-Raf kinase. This mutation leads to increased expression of interleukin (CXCL8), which plays a key role in cell growth and angiogenesis. Thus CXCL8 appears to be an interesting therapeutic target. Hence, we performed vaccination of mice with GST-CXCL8, which results in a reduced incidence of syngenic B16 melanoma cell xenograft tumors. We next addressed the molecular mechanisms responsible for aberrant CXCL8 expression in melanoma. The CXCL8 mRNA contains multiples AU-rich sequences (AREs) that modulate mRNA stability through the binding of tristetraprolin (TTP). Melanoma cell lines express very low TTP levels. We therefore hypothesized that the very low endogenous levels of TTP present in different melanoma cell lines might be responsible for the relative stability of CXCL8 mRNAs. We show that TTP is actively degraded by the proteasome and that extracellularregulated kinase inhibition results in TTP accumulation. Conditional expression of TTP in A375 melanoma cells leads to CXCL8 mRNA destabilization via its 3′ untranslated regions (3′-UTR), and TTP overexpression reduces its production. In contrast, downregulation of TTP by short hairpin RNA results in upregulation of CXCL8 mRNA. Maintaining high TTP levels in melanoma cells decreases cell proliferation and autophagy and induces apoptosis. Sorafenib, a therapeutic agent targeting Raf kinases, decreases CXCL8 expression in melanoma cells through reexpression of TTP. We conclude that loss of TTP represents a key event in the establishment of melanomas through constitutive expression of CXCL8, which constitutes a potent therapeutic target.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Volume301
Issue number3
DOIs
Publication statusPublished - Sep 2011

Fingerprint

Tristetraprolin
RNA Stability
Melanoma
Down-Regulation
Proteins
Messenger RNA
Proto-Oncogene Proteins B-raf
raf Kinases
Cell Line
Experimental Melanomas
Mutation
Interleukins
Autophagy
3' Untranslated Regions
Proteasome Endopeptidase Complex
Heterografts
Small Interfering RNA

Keywords

  • CXCL8
  • Extracellular-regulated kinase
  • Phosphorylation

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

Cite this

Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells. / Bourcier, Christine; Griseri, Paola; Grépin, Renaud; Bertolotto, Corinne; Mazure, Nathalie; Pagès, Gilles.

In: American Journal of Physiology - Cell Physiology, Vol. 301, No. 3, 09.2011.

Research output: Contribution to journalArticle

Bourcier, Christine ; Griseri, Paola ; Grépin, Renaud ; Bertolotto, Corinne ; Mazure, Nathalie ; Pagès, Gilles. / Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells. In: American Journal of Physiology - Cell Physiology. 2011 ; Vol. 301, No. 3.
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