Investigation of the signaling pathways involved in the proliferative life span barriers in werner syndrome fibroblasts.
Werner syndrome (WS) fibroblasts enter replicative senescence after a reduced in vitro life span. Although this has been postulated as causal in the accelerated aging seen in this disease, controversy remains as to whether WS is showing the acceleration of a normal cellular aging mechanism or, instead, the occurrence of a novel WS-specific process. To address this, we analyzed the signaling pathways involved in senescence in WS fibroblasts. Cultured WS fibroblasts underwent senescence after approximately 20 population doublings, with the majority of the cells having a 2N DNA content. This was associated with high levels of the CdkIs p16 and p21. Senescent WS cells reentered the cell cycle after microinjection of a p53-neutralizing antibody. Similarly, presenescent WS fibroblasts expressing the E6 and/or E7 oncoproteins bypassed M1 and ultimately reached a second proliferative life span barrier, which strongly resembled the second life span barriers found in normal cells for growth dynamics, cellular morphology, and expression of p16 and p21. The strong similarity between the signaling pathways triggering cell cycle arrest in WS and normal fibroblasts provides support for the defect in WS causing the acceleration of a normal aging mechanism and validates the use of WS as a model for some aspects of human aging.
Davis
Terence
T
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, Wales. davist2@cardiff.ac.uk
Faragher
Richard G A
RG
Jones
Christopher J
CJ
Kipling
David
D
D000375:Aging; D002453:Cell Cycle; D002455:Cell Division; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D016193:G1 Phase; D006801:Humans; D016196:S Phase; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics*
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D004247:DNA