Replicative senescence of human fibroblasts: the role of Ras-dependent signaling and oxidative stress.
Replicative senescence of human fibroblasts is a widely used cellular model for human aging. While it is clear that telomere erosion contributes to the development of replicative senescence, it is assumed that additional factors contribute to the senescent phenotype. The free radical theory of aging suggests that oxidative damage is a major cause of aging; furthermore, the expression of activated oncogenes, such as oncogenic Ras, can induce premature senescence in primary cells. The functional relation between the various inducers of senescence is not known. The present study was guided by the hypothesis that constitutive activation of normal, unmutated Ras may contribute to senescence-induced growth arrest in senescent human fibroblasts. When various branches of Ras-dependent signaling were investigated, constitutive activation of the Ras/Raf/MEK/ERK pathway was not observed. To evaluate the role of oxidative stress for the senescent phenotype, we also investigated stress-related protein kinases. While we found no evidence for alterations in the activity of p38, we could detect an increased activity of Jun kinase in senescent fibroblasts. We also found higher levels of reactive oxygen species (ROS) in senescent fibroblasts compared to their younger counterparts. The accumulation of ROS in senescent cells may be related to the constitutive activation of Jun kinase.
Hütter
Eveline
E
Institut für Biomedizinische Alternsforschung der Osterreichischen Akademie der Wissenschaften, Rennweg 10, A-6020 Innsbruck, Austria.
Unterluggauer
Hermann
H
Uberall
Florian
F
Schramek
Herbert
H
Jansen-Dürr
Pidder
P
D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D017382:Reactive Oxygen Species; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins