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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
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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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1 retracted
Chandrasekar, N., Mohanam, S., Gujrati, M., Olivero, W. C., Dinh, D. H., & Rao, J. S. (2003) · Oncogene · doi:10.1038/sj.onc.1206164 · Cited by 101
RetractedA biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477
The phosphatidylinositol 3-Kinase–AKT pathway in human cancer
Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,155
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218 · cited 1×
“6 ), is upregulated in ageing fibroblasts in vivo and in vitro , and is considered a marker of replicative senescenc”
Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization
Diehl, J. A., Cheng, M., Roussel, M. F., & Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.22.3499 · Cited by 2,130
Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis
Chen, Z., Trotman, L. C., Shaffer, D., Lin, H.-K., Dotan, Z. A., Niki, M., Koutcher, J. A., Scher, H. I., Ludwig, T., Gerald, W., et al. (2005) · Nature · doi:10.1038/nature03918 · Cited by 1,993
Friends or foes — bipolar effects of the tumour stroma in cancer
Mueller, M. M., & Fusenig, N. E. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1477 · Cited by 1,817
The RB and p53 pathways in cancer
Sherr, C. J., & McCormick, F. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00102-2 · Cited by 1,690
G1 cell-cycle control and cancer
Massagué, J. (2004) · Nature · doi:10.1038/nature03094 · Cited by 1,251
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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).”
BackgroundA complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,351
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232
Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086
“Furthermore, two other secreted factors, PAI-1 and WNT-2, have been implicated in senescence (Kortlever et al., 2006; Ye et al., 2007).”
BackgroundThe essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038
“Likewise, the ECM regulator PAI-1 has been shown to mediate senescence (Kortlever et al. 2006), although clinical data seem to point to a more complex picture (Kuilman and Peeper 2009).”
BackgroundFour faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,070
“2; Kortlever et al., 2006; Acosta et al., 2008; Kuilman et al., 2008).”
Chemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.038 · Cited by 1,801
“Secreted factors such as PAI-1 (Kortlever et al., 2006) and IGFBP7 (Wajapeyee et al., 2008) also contribute to senescent growth arrest.”
BackgroundInfluentialMechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622
“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).”
BackgroundBerns, K., Horlings, H. M., Hennessy, B. T., Madiredjo, M., Hijmans, E. M., Beelen, K., Linn, S. C., Gonzalez-Angulo, A. M., Stemke-Hale, K., Hauptmann, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.030 · Cited by 1,627
“Importantly, a second, independent shRNA knocking down PTEN expression (Kortlever et al., 2006) also conferred resistance to trastuzumab, effectively ruling out the possibility that ‘‘off target’’ effects of the shRNA vectors caused the resistance phenotype (Figure 2A).”
BackgroundLaberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3195 · Cited by 1,160
P53 in survival, death and metabolic health: a lifeguard with a licence to kill.
Kruiswijk, F., Labuschagne, C. F., & Vousden, K. H. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4007 · Cited by 1,080
Autophagy mediates the mitotic senescence transition
Young, A. R. J., Narita, M., Ferreira, M., Kirschner, K., Sadaie, M., Darot, J. F. J., Tavaré, S., Arakawa, S., Shimizu, S., Watt, F. M., et al. (2009) · Genes & Development · doi:10.1101/gad.519709 · Cited by 1,078
Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., Premsrirut, P., Luo, W., Chicas, A., Lee, C. S., et al. (2011) · Genes & Development · doi:10.1101/gad.17276711 · Cited by 1,046
“Depending on the biological context, this process can facilitate tumor regression or the resolution of wound healing responses (Xue et al. 2007; Krizhanovsky et al. 2008).”
BackgroundInfluentialFreund, A., Patil, C. K., & Campisi, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.69 · Cited by 1,039
“Among the benefits, some SASP components reinforce the senescence growth arrest (Kortlever et al, 2006; Acosta et al, 2008; Kuilman et al, 2008; Wajapeyee et al, 2008).”
BackgroundcGAS is essential for cellular senescence
Yang, H., Wang, H., Ren, J., Chen, Q., & Chen, Z. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705499114 · Cited by 1,009
“Components of SASP not only serve as a marker of senescence, but also participate in the senescence process (13).”
BackgroundTargeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016
“In addition, p53 directly induces senescence by stabilizing fibrinogen activator inhibitor-1, a marker of senescent cells.(88) p53 also activates the transcription of genes that encode promyelocytic leukemia protein, leading to cellular senescence.”
BackgroundJun, J.-I., & Lau, L. F. (2010) · Nature Cell Biology · doi:10.1038/ncb2070 · Cited by 998
Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence
Li, T., Kon, N., Jiang, L., Tan, M., Ludwig, T., Zhao, Y., Baer, R., & Gu, W. (2012) · Cell · doi:10.1016/j.cell.2012.04.026 · Cited by 912
Senescence and apoptosis: dueling or complementary cell fates?
Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J., & van Deursen, J. M. (2014) · The EMBO Reports · doi:10.15252/embr.201439245 · Cited by 915
“First, the SASP can reinforce and maintain the senescent state in cell culture models of senescence [21,129–131].”
Senescence-messaging secretome: SMS-ing cellular stress
Kuilman, T., & Peeper, D. S. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2560 · Cited by 909
“demonstrated that it does have a fundamental role in replicative senescenc”
BackgroundExploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867
Self-citationHow the ageing microenvironment influences tumour progression
Fane, M., & Weeraratna, A. T. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0222-9 · Cited by 849
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855
“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 e…”
BackgroundOrjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K., & Campisi, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905299106 · Cited by 654
“In addition to being inflammatory mediators, IL-6 and IL-8 were recently shown to belong to a small number of secreted factors that also reinforce the senescence growth arrest through autocrine and paracrine mechanisms (15, 16, 18, 19).”
BackgroundTargeting cellular senescence with senotherapeutics: senolytics and senomorphics
Zhang, L. J., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022) · FEBS Journal · doi:10.1111/febs.16350 · Cited by 674
The dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588
Tumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 625
Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., Broz, D. K., Basak, S., Park, E. J., McLaughlin, M. E., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.035 · Cited by 533
“Thus, despite being highly impaired for transactivation of most p53 target genes, including the senescence-relevant targets p21 and Pai-1 (Brown et al., 1997; Kortlever et al., 2006) (Figure 4B), p53 can induce senescence in the context of oncogenic signals.”
Eichhorn, P. J. A., Gili, M., Scaltriti, M., Serra, V., Guzman, M., Nijkamp, W., Beijersbergen, R. L., Valero, V., Seoane, J., Bernards, R., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1740 · Cited by 499
Self-citationInside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462
p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
Davalos, A. R., Kawahara, M., Malhotra, G. K., Schaum, N., Huang, J., Ved, U., Beausejour, C. M., Coppe, J.-P., Rodier, F., & Campisi, J. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201206006 · Cited by 439
“However, recent findings identified secreted proteins that partly reinforce the arrest in an autocrine manner (Kortlever et al., 2006; Acosta et al., 2008; Kuilman et al., 2008; Wajapeyee et al., 2008).”
Coppé, J.-P., Patil, C. K., Rodier, F., Krtolica, A., Beauséjour, C. M., Parrinello, S., Hodgson, J. G., Chin, K., Desprez, P.-Y., & Campisi, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009188 · Cited by 455
“For example, some reinforce the senescence growth arrest in an autocrine manner [28,29,30,31].”
BackgroundMED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling
Huang, S., Hölzel, M., Knijnenburg, T., Schlicker, A., Roepman, P., McDermott, U., Garnett, M., Grernrum, W., Sun, C., Prahallad, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.035 · Cited by 430
Self-citationCellular senescence: a link between cancer and age-related degenerative disease?
Campisi, J., Andersen, J. K., Kapahi, P., & Melov, S. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.09.001 · Cited by 421
“Finally, the SASP includes factors that help reinforce the tumor suppressive senescence growth arrest [27,30–32].”
BackgroundCellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity
Palmer, A. K., Tchkonia, T., LeBrasseur, N. K., Chini, E. N., Xu, M., & Kirkland, J. L. (2015) · Diabetes · doi:10.2337/db14-1820 · Cited by 423
“Decreased PAI-1, either by small interfering RNA knockdown or SIRT1 repression, results in decreased senescent cells (75,76).”
BackgroundSirt1 modulates premature senescence-like phenotype in human endothelial cells
Ota, H., Akishita, M., Eto, M., Iijima, K., Kaneki, M., & Ouchi, Y. (2007) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2007.08.008 · Cited by 429
“A recent study has revealed that PAI-1 is a direct downstream target gene of p53 and a major player in the induction of cellular senescence [40].”
BackgroundIannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20130783 · Cited by 414
Biomarkers of cellular senescence and skin aging
Wang, A. S., & Dreesen, O. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00247 · Cited by 404
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395
“senescence to different neighboring cell types [153,154,263,271,272,358].”
BackgroundCritical pathways in cellular senescence and immortalization revealed by gene expression profiling
Fridman, A. L., & Tainsky, M. A. (2008) · Oncogene · doi:10.1038/onc.2008.213 · Cited by 385
“Other markers of cellular senescence include p16INK4a, p21CIP1/WAF1, PAI-1, phosphorylated H2AX, activated CHK1 and CHK2 (Suzuki et al., 2001; d’Adda di Fagagna et al., 2003).”
BackgroundInfluentialBrady, C. A., & Attardi, L. D. (2010) · Journal of Cell Science · doi:10.1242/jcs.064501 · Cited by 400
“C 1 40 60 95 100 300 325 356 393 TAD1 TAD2 PRD DNA binding Tet p53 p53 Post-translational modifications of p53 and MDM2 DNA damage Nucleotide depletion Telomere attrition *Oncogene expression Oxidative stress Nutrient deprivation Hypoxia *Ribosomal dysfunction • Ubiquitylation • Binding and masking of TAD Binding Bind…”
BackgroundCellular senescence: putting the paradoxes in perspective
Campisi, J. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.005 · Cited by 368
p53mutations in colorectal cancer- molecular pathogenesis and pharmacological reactivation
Li, X.-L. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i1.84 · Cited by 384
p53-Mediated Hematopoietic Stem and Progenitor Cell Competition
Bondar, T., & Medzhitov, R. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.03.002 · Cited by 342
“For example, regulation of expression of PAI-1 by p53 is essential for p53-mediated senescence (Kortlever et al., 2006).”
p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence
Fujita, K., Mondal, A. M., Horikawa, I., Nguyen, G. H., Kumamoto, K., Sohn, J. J., Bowman, E. D., Mathe, E. A., Schetter, A. J., Pine, S. R., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1928 · Cited by 336
“Also examined by qRT-PCR were PAI-1 (plasminogen activator inhibitor-1; ref”
MethodBeyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication
Funcke, J., & Scherer, P. E. (2019) · Journal of Lipid Research · doi:10.1194/jlr.r094060 · Cited by 357
TGF-β signaling in tissue fibrosis: Redox controls, target genes and therapeutic opportunities
Samarakoon, R., Overstreet, J. M., & Higgins, P. J. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.10.003 · Cited by 340
Self-citationHealing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence
Adams, P. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.021 · Cited by 326
Tumor-Suppressor Functions of the TP53 PathwayPreprint
Aubrey, B. J., Strasser, A., & Kelly, G. L. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026062 · Cited by 352
“The TP53 protein controls cellular senescence by activating a number of transcriptional targets that include Cdkn1a, Pml, Pai1, and E2f7 (Pearson et al. 2000; Kortlever et al. 2006; Aksoy et al. 2012), some of which (e.g., Cdkn1a) are notable for additional function in cell-cycle regulation.”
BackgroundAbuetabh, Y., Wu, H. H., Chai, C., Yousef, H. A., Persad, S., Sergi, C. M., & Leng, R. P. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00863-4 · Cited by 280
Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence
Vaughan, D. E., Rai, R., Khan, S. S., Eren, M., & Ghosh, A. K. (2017) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.117.309451 · Cited by 258
“ing for the first time that PAI-1 is a marker and mediator of replicative senescence.(38) The authors concluded that regulation”
Cellular senescence and SASP in tumor progression and therapeutic opportunities
Dong, Z., Luo, Y., Yuan, Z., Tian, Y., Jin, T., & Feng, X. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02096-7 · Cited by 315
“Conversely, p53 knockout and PAI-1 over-expression induce CS [123].”
BackgroundPhysiological and pathological consequences of cellular senescence
Burton, D. G. A., & Krizhanovsky, V. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1691-3 · Cited by 253
“Plasminogen activator inhibitor-1 (PAI1) is elevated in Klotho-deficient mice and is a known regulator of cell senescence [78, 79].”
BackgroundOncogene-induced senescence: the bright and dark side of the response
Gorgoulis, V. G., & Halazonetis, T. D. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.07.013 · Cited by 257
Cellular senescence controls fibrosis in wound healing
Jun, J.-I., & Lau, L. F. (2010) · Aging · doi:10.18632/aging.100201 · Cited by 255
“For example, overexpression of the plasminogen activator inhibitor-1 (PAI-1) is sufficient to drive fibroblasts into senescence in vitro [24].”
BackgroundUtilizing RNA interference to enhance cancer drug discovery
Iorns, E. J., Lord, C. J., Turner, N. C., & Ashworth, A. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2355 · Cited by 251
Aging, Cellular Senescence, and Alzheimer’s Disease
Liu, R.-M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23041989 · Cited by 267
Hoenicke, L., & Zender, L. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs124 · Cited by 248
Malaquin, N., Martinez, A., & Rodier, F. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.05.010 · Cited by 247
“…to reinforce the SAGA in an autocrine or paracrine manner (Acosta et al., 2013; Chen et al., 2015; Herranz et al., 2015; Hubackova et al., 2012; Kim et al., 2007; Kortlever et al., 2006; Kuilman et al., 2008; Kuilman and Peeper, 2009; Wajapeyee et al., AC C EP TE D M AN U SC R IP T 7/37 2008).”
Jiang, C., Liu, G., Luckhardt, T., Antony, V., Zhou, Y., Carter, A. B., Thannickal, V. J., & Liu, R. (2017) · Aging Cell · doi:10.1111/acel.12643 · Cited by 234
MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis
Nagpal, V., Rai, R., Place, A. T., Murphy, S. B., Verma, S. K., Ghosh, A. K., & Vaughan, D. E. (2016) · Circulation · doi:10.1161/circulationaha.115.018174 · Cited by 248
“of cell proliferation, p53 also negatively regulates the production of extracellular matrix proteins.(15,16,38,39) Additionally, the”
BackgroundGranule exocytosis mediates immune surveillance of senescent cells
Sagiv, A., Biran, A., Yon, M., Simon, J., Lowe, S. W., & Krizhanovsky, V (2013) · Oncogene · doi:10.1038/onc.2012.206 · Cited by 240
Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning
Efimenko, A. Y., Евгеньевна, С. Е., Kalinina, N., & Stolzing, A. (2011) · Journal of Translational Medicine · doi:10.1186/1479-5876-9-10 · Cited by 230
“PAI-1 is a downstream target of p53 and is involved in regulating growth factor signalling [57].”
BackgroundMarine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228
“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).”
BackgroundYe, X., Zerlanko, B. J., Kennedy, A. L., Gowrishankar, B., Zhang, R., & Adams, P. D. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.034 · Cited by 237
“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).”
BackgroundHölzel, M., Huang, S., Köster, J., Øra, I., Lakeman, A., Caron, H. N., Nijkamp, W., Xie, J., Callens, T., Asgharzadeh, S., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.004 · Cited by 225
Self-citationSenescence: a new weapon for cancer therapy
Acosta, J. C., & Gil, J. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.11.006 · Cited by 235
Kumamoto, K., Spillare, E. A., Fujita, K., Horikawa, I., Yamashita, T., Appella, E., Nagashima, M., Takenoshita, S., Yokota, J., & Harris, C. C. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2780 · Cited by 231
Emerging roles of extracellular vesicles in cellular senescence and aging
Takasugi, M. (2018) · Aging Cell · doi:10.1111/acel.12734 · Cited by 227
Ng, K. W., Khoo, S., Heng, B. C., Setyawati, M. I., Tan, E. C., Zhao, X., Xiong, S., Fang, W., Leong, D. T., & Loo, S. C. J. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.07.036 · Cited by 221
“The BJ cell line is also amenable to introduction of specific genetic changes for more controlled experimental setup [29].”
BackgroundKennedy, A. L., Morton, J. P., Manoharan, I., Nelson, D. M., Jamieson, N. B., Pawlikowski, J. S., McBryan, T., Doyle, B., McKay, C., Oien, K. A., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.020 · Cited by 213
“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
Wu, D., & Prives, C. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.187 · Cited by 215
Young, A. R. J., & Narita, M. (2009) · The EMBO Reports · doi:10.1038/embor.2009.22 · Cited by 214
“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
Chen, H., Ruiz, P. D., McKimpson, W. M., Novikov, L., Kitsis, R. N., & Gamble, M. J. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.011 · Cited by 205
“Several of the SASP factors can independently trigger senescence in a paracrine fashion (Acosta et al., 2008b; Kortlever et al., 2006; Kuilman et al., 2008; Wajapeyee et al., 2008).”
Tumour suppression by p53: the importance of apoptosis and cellular senescence
Zuckerman, V., Wolyniec, K., Sionov, R. V., Haupt, S., & Haupt, Y. (2009) · The Journal of Pathology · doi:10.1002/path.2584 · Cited by 222
“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].”
BackgroundKim, K. S., Seu, Y. B., Baek, S.-H., Kim, M. J., Kim, K. J., Kim, J. H., & Kim, J.-R. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-03-0280 · Cited by 199
“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
Soto-Gamez, A., & Demaria, M. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2017.01.004 · Cited by 192
Cellular Senescence in Postmitotic Cells: Beyond Growth Arrest
Sapieha, P., & Mallette, F. A. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.03.003 · Cited by 193
Raabe, E. H., Lim, K. S., Kim, J. M., Meeker, A. K., Mao, X., Nikkhah, G., Maciaczyk, J., Kahlert, U. D., Jain, D., Bar, E. E., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-3349 · Cited by 199
“Immunoblotting showed increased expression of the senescence-associated markers p16INK4a (15) and PAI-1 (30) in BRAFV600E-transduced cells as compared with controls (Fig.”
ResultInfluentialAblain, J., Rice, K. L., Soilihi, H., de Reyniès, A., Minucci, S., & de Thé, H. (2014) · Nature Medicine · doi:10.1038/nm.3441 · Cited by 200
Assessing cell and organ senescence biomarkers
de Jesus, B. B., & Blasco, M. A. (2012) · Circulation Research · doi:10.1161/circresaha.111.247866 · Cited by 187
Context-dependent effects of cellular senescence in cancer development.
Lecot, P., Alimirah, F., Desprez, P.-Y., Campisi, J., & Wiley, C. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.115 · Cited by 183
“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 192
“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
Mudhasani, R., Zhu, Z., Hutvágner, G., Eischen, C. M., Lyle, S. R., Hall, L. L., Lawrence, J. B., Imbalzano, A. N., & Jones, S. N. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200802105 · Cited by 180
Cunha, S. I., Pardali, E., Thorikay, M., Anderberg, C., Hawinkels, L. J. A. C., Goumans, M., Seehra, J. S., Heldin, C., ten Dijke, P., & Pietras, K. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20091309 · Cited by 177
“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 Klotho 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
“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
Takasugi, M., Yoshida, Y., & Ohtani, N. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13268 · Cited by 190
TGF-β, EMT, and resistance to anti-cancer treatment
Wang, X., Eichhorn, P. J. A., & Thiery, J. P. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.10.004 · Cited by 187
Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence
Nakamura, A. J., Chiang, Y. J., Hathcock, K. S., Horikawa, I., Sedelnikova, O. A., Hodes, R. J., & Bonner, W. M. (2008) · Epigenetics & Chromatin · doi:10.1186/1756-8935-1-6 · Cited by 168
“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).”
MethodElzi, D. J., Lai, Y., Song, M., Hakala, K., Weintraub, S. T., & Shiio, Y. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1120437109 · Cited by 154
“Ectopic expression of PAI-1 was sufficient to induce senescence in human and mouse fibroblasts (22).”
BackgroundInfluentialChinta, S. J., Lieu, C. A., DeMaria, M., Laberge, R. ‐., Campisi, J., & Andersen, J. K. (2013) · Journal of Internal Medicine · doi:10.1111/joim.12029 · Cited by 165
“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].”
Pavón, M. Á., Arroyo‐Solera, I., Céspedes, M. V., Casanova, I., León, X., & Mangues, R. (2016) · Oncotarget · doi:10.18632/oncotarget.10344 · Cited by 165
“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 172
Eischen, C. M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026096 · Cited by 161
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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