title: 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.
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.
authors.affiliation: Istituto di Clinica Medica Generale, Ematologia ed Immunologia Clinica, Universita' di Ancona, 60020 Ancona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Svegliati
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cancello
authors.forename: Paola
authors.initials: P
authors.lastname: Sambo
authors.forename: Michele
authors.initials: M
authors.lastname: Luchetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Paroncini
authors.forename: Guido
authors.initials: G
authors.lastname: Orlandini
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Discepoli
authors.forename: Roberto
authors.initials: R
authors.lastname: Paterno
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Santillo
authors.forename: Concetta
authors.initials: C
authors.lastname: Cuozzo
authors.forename: Silvana
authors.initials: S
authors.lastname: Cassano
authors.forename: Enrico V
authors.initials: EV
authors.lastname: Avvedimento
authors.forename: Armando
authors.initials: A
authors.lastname: Gabrielli
mesh_terms: D017209:Apoptosis; D015152:Blotting, Northern; D002478:Cells, Cultured; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000473:pathology*; D013997:Time Factors; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D018631:ras Proteins