Reinitiation of DNA Synthesis and Cell Division in Senescent Human Fibroblasts by Microinjection of Anti-p53 Antibodies
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In human fibroblasts, growth arrest at the end of the normal proliferative life span (induction of senescence) is dependent on the activity of the tumor suppressor protein p53. In contrast, once senescence has been established, it is generally accepted that reinitiation of DNA synthesis requires loss of multiple suppressor pathways, for example, by expression of Simian virus 40 (SV40) large T antigen, and that even this will not induce complete cell cycle traverse. Here we have used microinjection of monoclonal antibodies to the N terminus of p53, PAb1801 and DO-1, to reinvestigate the effect of blocking p53 function in senescent human fibroblasts. Unexpectedly, we found that both antibodies induce senescent cells to reenter S phase almost as efficiently as SV40, accompanied by a reversion to the "young" morphology. Furthermore, this is followed by completion of the cell division cycle, as shown by the appearance of mitoses, and by a four- to fivefold increase in cell number 9 days after injection. Immunofluorescence analysis showed that expression of the p53-inducible cyclin/kinase inhibitor p21sdi1/WAF1 was greatly diminished by targeting p53 with either PAb1801 or DO-1 but remained high and, moreover, still p53 dependent in cells expressing SV40 T antigen. As previously observed for induction, the maintenance of fibroblast senescence therefore appears to be critically dependent on functional p53. We suggest that the previous failure to observe this by using SV40 T-antigen mutants to target p53 was most probably due to incomplete abrogation of p53 function.
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Inactivation of p53 in at least some replicatively senescent human cells completely reverses the senescent growth arrest.
“Inactivation of p53 in at least some replicatively senescent human cells completely reverses the senescent growth arrest (Gire and Wynford-Thomas, 1998; Beausejour et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Gire and Wynford-Thomas, 1998
The initial senescence arrest is reversible because senescent cells that express low levels of p16 can re-enter the cell cycle upon p53 inactivation.
“This initial arrest is reversible because senescent cells that express low levels of p16 can re-enter the cell cycle upon p53 inactivation [47,48].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [47]
Continuous DNA damage signaling is essential for maintenance of cell cycle arrest in senescence because inactivation of checkpoint kinases ATM, CHK2, and p53 results in escape from arrest.
“Continuous DNA damage signaling is essential for cell cycle arrest maintenance because inactivation of checkpoint kinases, such as ATM [10,12], CHK2 [11], and p53 [47,48], results in escape from this arrest.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [47]
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- Authors
- Gire, V., & Wynford-Thomas, D.
- Affiliations
- Cancer Research Campaign Laboratories, Department of Pathology, University of Wales College of Medicine, Cardiff CF4 4XN, United Kingdom
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1998-03-01
- Volume
- 18
- Issue
- 3
- Pages
- 1611-1621
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC108876
- OpenAlex
- W2163386603
- Cited by
- 161
- References
- 63
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 7
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- 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, p53, human fibroblasts, cell cycle re-entry, SV40 large T antigen, p21, cyclin-dependent kinase inhibitors, anti-p53 antibodies, growth arrest
- MeSH terms
- Antibodies, Monoclonal, Cell Division, Diploidy, DNA, Fibroblasts, Humans, Microinjections, Simian virus 40, Transcriptional Activation, Tumor Suppressor Protein p53, Cyclins, Cellular Senescence, Replication Origin, Cyclin-Dependent Kinase Inhibitor p21
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