Journal ArticleDOI
Bypass of Senescence After Disruption of p21CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts
TLDR
At the checkpoint between the prereplicative phase of growth and the phase of chromosome replication, cells lacking p21 failed to arrest the cell cycle in response to DNA damage, but their apoptotic response and genomic stability were unaltered.Abstract:
Most somatic cells die after a finite number of cell divisions, a phenomenon described as senescence. The p21 CIP1/WAF1 gene encodes an inhibitor of cyclin-dependent kinases. Inactivation of p21 by two sequential rounds of targeted homologous recombination was sufficient to bypass senescence in normal diploid human fibroblasts. At the checkpoint between the prereplicative phase of growth and the phase of chromosome replication, cells lacking p21 failed to arrest the cell cycle in response to DNA damage, but their apoptotic response and genomic stability were unaltered. These results establish the feasibility of using gene targeting for genetic studies of normal human cells.read more
Citations
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Journal ArticleDOI
Cellular senescence: when bad things happen to good cells
TL;DR: Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
Journal ArticleDOI
Requirement for p53 and p21 to Sustain G2 Arrest After DNA Damage
Fred Bunz,A. Dutriaux,Christoph Lengauer,Todd Waldman,Shibin Zhou,J. P. Brown,John M. Sedivy,Kenneth W. Kinzler,Bert Vogelstein +8 more
TL;DR: After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle but this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21.
Journal ArticleDOI
Blinded by the Light: The Growing Complexity of p53
Karen H. Vousden,Carol Prives +1 more
TL;DR: Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision that must be understood if the next generation of drugs that selectively activate or inhibit p53 are to be exploited efficiently.
Journal ArticleDOI
Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors
Judith Campisi,Judith Campisi +1 more
TL;DR: The senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
Journal ArticleDOI
Genome editing with engineered zinc finger nucleases
TL;DR: A broad range of outcomes has resulted from the application of the same core technology: targeted genome cleavage by engineered, sequence-specific zinc finger nucleases followed by gene modification during subsequent repair.
References
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Journal ArticleDOI
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Leonard Hayflick,P.S. Moorhead +1 more
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Journal ArticleDOI
Specific association of human telomerase activity with immortal cells and cancer
Nam Woo Kim,Mieczyslaw A. Piatyszek,Karen R. Prowse,Calvin B. Harley,Michael D. West,Peter L. C. Ho,Gina M. Coviello,Woodring E. Wright,Scott L. Weinrich,Jerry W. Shay +9 more
TL;DR: A highly sensitive assay for measuring telomerase activity was developed in this paper, which showed that telomerases appear to be stringently repressed in normal human somatic tissues but reactivated in cancer, where immortal cells are likely required to maintain tumor growth.
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A biomarker that identifies senescent human cells in culture and in aging skin in vivo
Goberdhan P. Dimri,X Lee,G Basile,Meileen Acosta,G Scott,C Roskelley,E E Medrano,Maarten H.K. Linskens,Ivica Rubelj,Olivia M. Pereira-Smith +9 more
TL;DR: It is shown that several human cells express a beta-galactosidase, histochemically detectable at pH 6, upon senescence in culture, which provides in situ evidence that senescent cells may exist and accumulate with age in vivo.
Journal ArticleDOI
Telomeres shorten during ageing of human fibroblasts.
TL;DR: The amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo.