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Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence
Open accessAbstract
p53 limits the proliferation of primary diploid fibroblasts by inducing a state of growth arrest named replicative senescence - a process which protects against oncogenic transformation and requires integrity of the p53 tumour suppressor pathway. However, little is known about the downstream target genes of p53 in this growth-limiting response. Here, we report that suppression of the p53 target gene encoding plasminogen activator inhibitor-1 (PAI-1) by RNA interference (RNAi) leads to escape from replicative senescence both in primary mouse embryo fibroblasts and primary human BJ fibroblasts. PAI-1 knockdown results in sustained activation of the PI(3)K-PKB-GSK3beta pathway and nuclear retention of cyclin D1, consistent with a role for PAI-1 in regulating growth factor signalling. In agreement with this, we find that the PI(3)K-PKB-GSK3beta-cyclin D1 pathway is also causally involved in cellular senescence. Conversely, ectopic expression of PAI-1 in proliferating p53-deficient murine or human fibroblasts induces a phenotype displaying all the hallmarks of replicative senescence. Our data indicate that PAI-1 is not merely a marker of senescence, but is both necessary and sufficient for the induction of replicative senescence downstream of p53.
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In the citing paper
“Early studies showed that late passage human fibroblasts or fibroblasts derived from subjects with premature aging syndromes produce secretory proteins, including plasminogen activator inhibitor type-1 (PAI-1), which later became a functional marker of senescence (Murano et al. 1991; Goldstein et al. 1994; Kortlever et al. 2006).”
From Cellular senescence and its effector programs (2014) · cites this paper as Kortlever et al. 2006
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In mouse cells, the SASP factor PAI-1 (plasminogen activator inhibitor 1) reinforces replicative senescence (137).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [137]
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In the citing paper
“Specific components of the SASP such as IGFBP-7, PAI-1, IL-6 and CXCR2-binding chemokines (such as IL-8 or GRO α ) can reinforce senescence 8-11 .”
From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [10]
In the citing paper
“Importantly, overexpression of PAI-1 is sufficient to induce replicative senescence as indicated by SA-βgal activity in mouse embryonic fibroblasts (75).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [75]
In the citing paper
“PAI-1 is a critical downstream target of p53 involved in inducing replicative senescence via PI(3)K-PKB-GSK3β-cyclin D1 pathway (Kortlever et al., 2006).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kortlever et al., 2006
In the citing paper
“Therefore, different components of SASP can reinforce the senescent state by amplifying or transmitting SASP via autocrine or paracrine signaling pathways (Kortlever et al., 2006; Acosta et al., 2008; Kuilman et al., 2008; Wajapeyee et al., 2008; Zhang et al., 2018).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kortlever et al., 2006
In the citing paper
“Other secreted proteins, such as IGFBP7 that influences MAPK signaling [271] and PAI-1 [272] that regulates the phosphoinositide 3-kinase (PI3K) pathway, also contribute to senescence stabilization by inhibiting proliferative and mitogenic pathways.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [272]
In the citing paper
“Many SASP factors exert tumor-suppressive activities through autocrine and paracrine signaling cascades that enforce senescence cell cycle exit and transmit senescence to different neighboring cell types [153,154,263,271,272,358].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [272]
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Cited by
Sorted by citations
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
“Like the CXCR-2 cytokines, PAI-1 also seems to reinforce the senescence growth arrest (88).”
BackgroundCoppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302
“The SASP can be beneficial because some SASP components reinforce the senescent growth arrest by an autocrine cytokine network [37,38,40,41], thereby contributing to maintenance of the senescence growth arrest.”
BackgroundBlinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163
“As with other p53 responses, senescence is likely to result from changes in the expression of a number of proteins such as the plasminogen activator inhibitor 1 (PAI-1) (Kortlever et al., 2006; Leal et al., 2008).”
BackgroundAging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954
“In mouse cells, the SASP factor PAI-1 (plasminogen activator inhibitor 1) reinforces replicative senescence (137).”
BackgroundThe Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,584
“p21 and PAI-1, both regulated by p53, are implicated in protection of cancer and other cell types from apoptosis (Gartel & Radhakrishnan, 2005; Kortlever et al., 2006; Schneider et al., 2008; Vousden & Prives, 2009).”
Background
Metadata
- Authors
- Kortlever, R. M., Higgins, P. J., & Bernards, R.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Albany Medical College (US)
- Corresponding author
- Bernards, René
- Venue
- Nature Cell Biology
- Published
- 2006-07-23
- Volume
- 8
- Issue
- 8
- Pages
- 877-884
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2954492
- OpenAlex
- W1978888457
- Cited by
- 637
- References
- 45
- Citations by year
- 2026: 28 · 2025: 27 · 2024: 23 · 2023: 36 · 2022: 35 · 2021: 32 · 2020: 35 · 2019: 29 · 2018: 31 · 2017: 34 · 2016: 29 · 2015: 27 · 2014: 36 · 2013: 27 · 2012: 34
- FWCI
- 18.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- KWF Kankerbestrijding
- National Institutes of Health
- National Institute of General Medical Sciences (GM57242, R01GM057242)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
- plasminogen activator inhibitor-1, p53, replicative senescence, cellular senescence, cyclin D1, p53 target genes, fibroblasts, tumor suppressor pathways, growth arrest, oncogenic transformation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cells, Cultured, Cisplatin, DNA Damage, Embryo, Mammalian, Fibroblasts, Humans, Microscopy, Fluorescence, Mutation, Blotting, Western, Tumor Suppressor Protein p53, Cellular Senescence, Plasminogen Activator Inhibitor 1, Phosphatidylinositol 3-Kinases, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Protein p14ARF, RNA Interference, Glycogen Synthase Kinase 3, NIH 3T3 Cells, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Proto-Oncogene Proteins c-akt, Cyclin-Dependent Kinase 4, Mice
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