Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence
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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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Late passage human fibroblasts or fibroblasts from subjects with premature aging syndromes produce secretory proteins including PAI-1, which later became a functional marker of senescence.
“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
The Abstract (page unavailable) says PAI-1 is upregulated in ageing human fibroblasts and is a marker of senescence; it also reports a causal role for PAI-1 in senescence. The paper does not address fibroblasts from subjects with premature-aging syndromes, so it does not support that part of the sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn mouse cells, the SASP factor PAI-1 reinforces replicative senescence.
“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]
Specific components of the SASP such as IGFBP-7, PAI-1, IL-6 and CXCR2-binding chemokines can reinforce senescence.
“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]
Overexpression of PAI-1 is sufficient to induce replicative senescence, as indicated by SA-βgal activity in mouse embryonic fibroblasts.
“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]
PAI-1 is a critical downstream target of p53 involved in inducing replicative senescence via PI(3)K-PKB-GSK3β-cyclin D1 pathway.
“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
Different components of SASP can reinforce senescent state by amplifying or transmitting SASP via autocrine or paracrine signaling pathways.
“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
IGFBP7 influences MAPK signaling and PAI-1 regulates PI3K pathway, and both contribute to senescence stabilization by inhibiting proliferative and mitogenic pathways.
“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]
Many SASP factors exert tumor-suppressive activities through autocrine and paracrine signaling cascades that enforce senescence cell cycle exit and transmit senescence to neighboring cell types.
“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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p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
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“Key targets are the proapoptotic genes Bax, Puma and Noxa (Michalak et al., 2005), the genes encoding the cell cycle regulators p21 (el-Deiry et al., 1993) and Ptprv (Doumont et al., 2005) and the senescence-inducing gene Plasminogen activator inhibitor 1 (Kortlever et al., 2006).”
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“Recently, Bernards and coworkers showed that the secreted extracellular factor, plasminogen activator inhibitor-1 (PAI-1), contributes to senescence in mouse and human fibroblasts (Kortlever et al., 2006).”
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“The BJ cell line is also amenable to introduction of specific genetic changes for more controlled experimental setup [29].”
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“We and others have previously shown that activation of GSK3b kinase contributes to onset of senescence (Kortlever et al., 2006; Liu et al., 2008; Ye et al., 2007; Zmijewski and Jope, 2004).”
InfluentialRelevance of the p53–MDM2 axis to aging
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“Kortlever et al (2006) identified plasminogen activator inhibitor 1 (PAI1), another classical marker of senescence, as having a crucial role in the induction of replicative senescence downstream of p53.”
BackgroundCellular senescence: the sought or the unwanted?
Sun, Y., Coppé, J.-P., & Lam, E. W.-F. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.08.002 · Cited by 208 · see citing works
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Tumour suppression by p53: the importance of apoptosis and cellular senescence
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“Importantly, downregulation of PAI-1 results in escape from replicative senescence in murine and human primary fibroblasts, through sustained activation of the PI3K–Akt survival pathway and nuclear retention of Cyclin D [63].”
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“Human umbilical vein endothelial cells (HUVECs) and endothelial cell basal medium-2 (EBM-2) containing several growth factors and supplements (EGM-2) were purchased from Cambrex Bio Science (Walkersville, MD). p16- or p53-null mouse embryo fibroblasts (MEFs) were provided by Dr. H. W. Lee (Yonsei University, Korea).”
BackgroundInfluentialTherapeutic interventions for aging: the case of cellular senescence
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Cellular Senescence in Postmitotic Cells: Beyond Growth Arrest
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“Immunoblotting showed increased expression of the senescence-associated markers p16INK4a (15) and PAI-1 (30) in BRAFV600E-transduced cells as compared with controls (Fig.”
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“SASP factors include pro-inflammatory cytokines, chemokines, growth factors and proteases (Kortlever et al, 2006; Acosta et al, 2008; Wajapeyee et al, 2008).”
BackgroundHepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives
Zhang, M., Salas, S. S., Damba, T., Borghesan, M., Demaria, M., & Moshage, H. J. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111572 · Cited by 180 · see citing works
“Plasminogen activator inhibitor (PAI)-1 is necessary and sufficient for the induction of senescence (Kortlever et al., 2006).”
Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells
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“Even though there are results reporting cytostatic and antimigratory properties of PAI-1 in fibroblasts (Deng et al., 1996; Kortlever et al., 2006; Kortlever et al., 2008), a recent study using PAI-1–deficient mice convincingly demonstrates that tumors devoid of host-derived PAI-1 are very poorly…”
BackgroundPAI-1–regulated extracellular proteolysis governs senescence and survival in <i>Klotho</i> mice
Eren, M., Boe, A. E., Murphy, S. B., Place, A. T., Nagpal, V., Morales-Nebreda, L., Urich, D., Quaggin, S. E., Budinger, G. R. S., Mutlu, G. M., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321942111 · Cited by 176 · see citing works
“Because PAI-1 is necessary and sufficient to induce replicative senescence in vitro downstream of p53 (19) and is markedly increased in kl/kl mice, we hypothesized that PAI-1 is a critical determinant of the phenotypic abnormalities developed by kl/kl mice.”
BackgroundCellular senescence and the tumour microenvironment
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Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence
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“WI-38 cells at 57 PDs, BJ cells at 70–72 PDs, MEFs at 7–9 PDs and TERT-null MEFs at 9 PDs were used as high PDs [19,30,40] (see Additional file 1 for experimental detail).”
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“Ectopic expression of PAI-1 was sufficient to induce senescence in human and mouse fibroblasts (22).”
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“These factors include the cytokines IL-6 and IL-8, the protease inhibitor plasminogen activator inhibitor-1 and the pleiotropic protein insulin-like growth factor binding protein-7 [43, 44, 48, 49].”
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“Its expression could also be modulated by several transcription factors such as SP1, AP1, SMAD proteins, TGF-β1, and p53 [44-46].”
BackgroundNrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome
Hiebert, P., Wietecha, M. S., Cangkrama, M., Haertel, E., Mavrogonatou, E., Stumpe, M., Steenbock, H., Grossi, S., Beer, H., Angel, P. E., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.06.012 · Cited by 166 · see citing works
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- 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
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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