Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts
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.
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Inactivation of the gene encoding p21 causes cells to bypass telomere-dependent replicative senescence and enter crisis.
“Likewise, inactivation of the gene encoding p21, a target for p53 transactivation and inhibitor of cell cycle progression, causes cells to bypass telomere-dependent replicative senescence and enter crisis (Brown et al., 1997).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Brown et al., 1997
Complete bypass of telomere shortening-induced senescence in human cells requires inactivation of multiple pathways, making this proliferation barrier robust.
“Because the complete bypass of telomere shortening-induced senescence in human cells requires the inactivation of multiple pathways, this mechanism of curbing the proliferation of transformed cells is likely to be robust43,45–48.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [48]
Replicative senescence is bypassed upon loss of p21 but not upon loss of p16 function.
“Replicative senescence is bypassed upon loss of p21 [41] but not upon loss of p16 function [45,46].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [41]
Inactivation of p21 allows human senescing fibroblasts to override senescence arrest and extends their proliferative potential, probably because in these cells CDK2 activity cannot be sufficiently reduced.
“Inactivation of p21 allows human senescing fibroblasts to override senescence arrest and extends their proliferative potential, probably because in these cells CDK2 activity cannot be sufficiently reduced [41,42].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [41]
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- Authors
- Brown, J. P., Wei, W., & Sedivy, J. M.
- Affiliations
- Brown University (US)
- Corresponding author
- Brown, Jeremy P.
- Sedivy, John M.
- Venue
- Science
- Published
- 1997-08-08
- Volume
- 277
- Issue
- 5327
- Pages
- 831-834
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1992934869
- Cited by
- 804
- References
- 31
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 19 · 2021: 17 · 2020: 13 · 2019: 17 · 2018: 22 · 2017: 16 · 2016: 30 · 2015: 20 · 2014: 29 · 2013: 36 · 2012: 28
- FWCI
- 26.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 41690, R01GM041690)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, p21 CIP1/WAF1, cyclin-dependent kinase inhibitors, homologous recombination, gene targeting, human diploid fibroblasts, DNA damage checkpoint, cell cycle arrest, apoptosis, genome stability, cell immortalization
- MeSH terms
- Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Cell Division, Cells, Cultured, Dihydroorotase, DNA Damage, Fibroblasts, Genetic Vectors, Humans, Multienzyme Complexes, G1 Phase, Cyclins, Telomere, Cellular Senescence, Apoptosis, Gene Deletion, Electroporation, Gene Targeting, Cyclin-Dependent Kinase Inhibitor p21
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