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.
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.
Svegliati
Silvia
S
Istituto di Clinica Medica Generale, Ematologia ed Immunologia Clinica, Universita' di Ancona, 60020 Ancona, Italy.
Cancello
Raffaella
R
Sambo
Paola
P
Luchetti
Michele
M
Paroncini
Paolo
P
Orlandini
Guido
G
Discepoli
Giancarlo
G
Paterno
Roberto
R
Santillo
Mariarosaria
M
Cuozzo
Concetta
C
Cassano
Silvana
S
Avvedimento
Enrico V
EV
Gabrielli
Armando
A
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*
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