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Investigation of the signaling pathways involved in the proliferative life span barriers in Werner syndrome fibroblasts

Davis, Terence, Faragher, Richard G. A., Jones, Christopher J. and Kipling, David Glyn 2004. Investigation of the signaling pathways involved in the proliferative life span barriers in Werner syndrome fibroblasts. Annals of the New York Academy of Sciences 1019 (1) , pp. 274-277. 10.1196/annals.1297.046

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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 ∼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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: aging; cyclin-dependent kinases; oncoproteins; p53; p21WAF1; p16INK4a; replicative senescence; telomerase; telomeres
Publisher: Wiley-Blackwell
ISSN: 0077-8923
Last Modified: 04 Jun 2017 04:57

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