Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2: Amplification of ROS and Ras in systemic sclerosis fibroblasts

Silvia Svegliati, Raffaelia Cancello, Paola Sambo, Michele Luchetti, Paolo Paroncini, Guido Orlandini, Giancarlo Discepoli, Roberto Paterno, Mariarosaria Santillo, Concetta Cuozzo, Silvana Cassano, Enrico V. Avvedimento, Armando Gabrielli

Research output: Contribution to journalArticlepeer-review

Abstract

The levels of Ras proteins in human primary fibroblasts are regulated by PDGF (platelet-derived growth factor). PDGF induced post-transcriptionally Ha-Ras by stimulating reactive oxygen species (ROS) and ERK1/2. Activation of ERK1/2 and high ROS levels stabilize Ha-Ras protein, by inhibiting proteasomal degradation. We found a remarkable example in vivo of amplification of this circuitry in fibroblasts derived from systemic sclerosis (scleroderma) lesions, producing vast excess of ROS and undergoing rapid senescence. High ROS, Ha-Ras, and active ERK1/2 stimulated collagen synthesis, DNA damage, and accelerated senescence. Conversely ROS or Ras inhibition interrupted the signaling cascade and restored the normal phenotype. We conclude that in primary fibroblasts stabilization of Ras protein by ROS and ERK1/2 amplifies the response of the cells to growth factors and in systemic sclerosis represents a critical factor in the onset and progression of the disease.

Original languageEnglish
Pages (from-to)36474-36482
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number43
DOIs
Publication statusPublished - Oct 28 2005

ASJC Scopus subject areas

  • Biochemistry

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