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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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Items 301–400 of 635
Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration
Hussain, M. S., Agrawal, N., Ilma, B., Rekha, M. M., Nayak, P. P., Kaur, M., Khachi, A., Goyal, K., Rekha, A., Gupta, S., et al. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70503 · Cited by 35
Bypassing cellular senescence by genetic screening tools
Vergel, M., & Carnero, A. (2010) · Clinical & Translational Oncology · doi:10.1007/s12094-010-0528-2 · Cited by 30
“Other genes that have been shown to induce a senescencelike phenotype include PPP1A [17, 60], SAHH [61, 62], Csn2, Arase and BRF1 [63], PGM [64], IGFBP3 and IG-FBPrP1 [65], PAI-1 [66, 67 ], MKK3 [68], MKK6 [68, 69], Smurf2 [70] and HIC-5 [71].”
BackgroundMolecular basis of senescence transmitting in the population of human endometrial stromal cells
Griukova, A., Deryabin, P. I., Shatrova, A. N., Burova, E., Severino, V., Farina, A., Nikolsky, N. N., & Borodkina, A. V. (2019) · Aging · doi:10.18632/aging.102441 · Cited by 32
“Increase in PAI-1 expression accompanies both replicative senescence and stress-induced senescence [30, 38].”
InfluentialHMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer’s disease pathology
Tanaka, H., Kondo, K., Fujita, K., Homma, H., Tagawa, K., Jin, X., Jin, M., Yoshioka, Y., Takayama, S., Masuda, H., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02671-4 · Cited by 33
Gene regulation and tumor suppression by the bromodomain-containing protein BRD7
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PAI-1 is a critical regulator of FGF23 homeostasis
Eren, M., Place, A. T., Thomas, P. M., Flevaris, P., Miyata, T., & Vaughan, D. E. (2017) · Science Advances · doi:10.1126/sciadv.1603259 · Cited by 31
Insights into 4E-BP1 and p53 mediated regulation of accelerated cell senescence
Chao, S. K., Horwitz, S. B., & McDaid, H. M. (2011) · Oncotarget · doi:10.18632/oncotarget.221 · Cited by 30
“Previously thought to be only a marker of the senescent phenotype, PAI-1, has been reported to be required for p53-mediated replicative senescence induction in primary mouse diploid fibroblasts and human BJ cells [30].”
BackgroundHiggins, S. P., Higgins, C. E., & Higgins, P. J. (2011) · International Journal of Cell Biology · doi:10.1155/2011/710974 · Cited by 30
“The present findings are consistent with these and previous data that TGF-β-initiated growth inhibition as well as senescence arrest is PAI-1-dependent [23, 27] and establish, moreover, PAI-1 as a mediator of NaB-initiated cytostasis.”
BackgroundResultInfluentialSelf-citationThe Power Behind the Throne: Senescence and the Hallmarks of Cancer
Hoare, M., & Narita, M. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030617-050352 · Cited by 33
Chen, L., Pastorino, F., Berry, P., Bonner, J. J., Kirk, C., Wood, K. M., Thomas, H. D., Zhao, Y., Daga, A., Veal, G. J., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.32058 · Cited by 30
Maynadier, M., Farnoud, M. R., Lamy, P., Laurent‐Matha, V., Garcia, M., & Rochefort, H. (2013) · International Journal of Oncology · doi:10.3892/ijo.2013.2095 · Cited by 32
Liu, Y., Cheng, Z., Pan, F., & Yan, W.-G. (2017) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/096504016x14813867762123 · Cited by 29
RetractedPan, X., Zhang, R., Xie, C., Gan, M., Yao, S., Yao, Y., Jin, J., Han, T., Huang, Y., Gong, Y., et al. (2017) · Europe PMC (PubMed Central) · Cited by 29
The Intricate Interplay between Mechanisms Underlying Aging and Cancer
Piano, A. (2014) · Aging and Disease · doi:10.14336/ad.2014.0209 · Cited by 28
“[223] Kortlever RM, Higgins PJ, Bernards R (2006).”
BackgroundInhibitory effect of phytol on cellular senescence
Jeong, S. H. (2018) · Biomedical Dermatology · doi:10.1186/s41702-018-0025-8 · Cited by 28
“The P53 protein regulates the expression levels of various cell cycle-related genes such as cyclin-dependent kinase inhibitor 1A (P21), 14-3-3σ, and CASP3 (Kortlever et al. 2006).”
BackgroundShrestha, N., Chaturvedi, P., Zhu, X., Dee, M. J., George, V., Janney, C., Egan, J. O., Liu, B., Foster, M., Marsala, L. I., et al. (2023) · Aging Cell · doi:10.1111/acel.13806 · Cited by 27
“PAI- 1 is not only a biomarker of cellular senescence but also is necessary and sufficient for replicative senescence downstream of p53 and is a key inducer of the senescence program (Hiebert et al., 2018; Kortlever et al., 2006).”
BackgroundLi, Q., Higgins, S. P., Lu, Q., Samarakoon, R., Wilkins-Port, C. E., Ye, Q., Higgins, C. E., Staiano‐Coico, L., & Higgins, P. J. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701068 · Cited by 28
“PAI-1 is also expressed at high levels in senescent cells where it likely interferes with uPA-dependent growth factor activation (Mu et al., 1998; Kortlever et al., 2006).”
BackgroundSelf-citationCzekay, R., Higgins, C. E., Aydin, H. B., Samarakoon, R., Subasi, N. B., Higgins, S. P., Lee, H., & Higgins, P. J. (2024) · Cells · doi:10.3390/cells13100796 · Cited by 27
“This has clinical implications as p53 is a critical co-activator of SERPINE1 transcription in the genomic profibrotic and cellular senescence programs [70,76–80].”
BackgroundSelf-citationKwon, I., Kim, J., Rhee, D., Kim, B.-O., & Pyo, S. (2017) · Toxicon · doi:10.1016/j.toxicon.2017.02.017 · Cited by 28
“PAI-1 has been identified as an inducer of senescence and a downstream target of p53 (Kortlever et al., 2006).”
BackgroundThe endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice
Bochenek, M. L., Bauer, T., Gogiraju, R., Nadir, Y., Mann, A., Schönfelder, T., Hünig, L., Brenner, B., Münzel, T. F., Wenzel, P., et al. (2018) · Blood Advances · doi:10.1182/bloodadvances.2017014050 · Cited by 27
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Sappino, A.-P., Buser, R., Seguin, Q., Fernet, M., Lesne, L., Gumy‐Pause, F., Reith, W., Favaudon, V., & Mandriota, S. J. (2012) · Oncogenesis · doi:10.1038/oncsis.2012.7 · Cited by 27
Suppression of the p53-Dependent Replicative Senescence Response by Lysophosphatidic Acid Signaling
Kortlever, R. M., Brummelkamp, T. R., van Meeteren, L. A., Moolenaar, W. H., & Bernards, R. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0066 · Cited by 27
“This leads to triggering of tumorsuppressive p19-p53 signaling, resulting in the induction of antiproliferative p53 targets, such as PAI-1 and p21 , and a cell cycle arrest (14-17).”
BackgroundSelf-citationLee, W., Jo, S. Y., Lee, M. H., Won, C. H., Lee, M. H., Choi, J. H., & Chang, S. E. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17060948 · Cited by 27
“Abbreviations SL solar lentigo MCP monocyte chemoattractant protein UVR ultraviolet radiation NHMs normal human melanocytes NHKs normal human keratinocytes SASP senescence-associated secretory phenotype IL interleukin SA-β-Gal senescence-associated beta-galactosidase PBS phosphate-buffered saline ELISA enzyme immunoso…”
BackgroundInfluentialde Souza, C. F., Xander, P. B., Monteiro, A. C., Silva, A. G. D. S., da Silva, D. C. P., Mai, S., Bernardo, V., Lopes, J. D., & Jasiulionis, M. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044800 · Cited by 27
“It is justified since SERPINE1 gene is a critical downstream target of P53 gene in the induction of replicative senescence [43].”
BackgroundEpigenetic alterations of the SERPINE1 gene in oral squamous cell carcinomas and normal oral mucosa
Gao, S., Nielsen, B. S., Krogdahl, A., Sørensen, J. A., Tagesen, J., Dabelsteen, S., Dabelsteen, E., & Andreasen, P. A. (2010) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20762 · Cited by 26
“…of PAI-1 in histologically normal mucosa adjacent to tumors may indicate cellular senescence as part of an early malignant development; this is in agreement with previous studies that have shown molecular changes in histologically normal mucosa adjacent to oral carcinomas (Kortlever et al., 2006).”
BackgroundResultHiggins, C. E., Tang, J., Higgins, S. P., Gifford, C. C., Mian, B. M., Jones, D., Zhang, W., Costello, A., Conti, D. J., Samarakoon, R., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.678524 · Cited by 25
“…largely by altering interaction of the PLAU-PLAU receptor (PLAUR) complex with its associated integrins and by functioning as a ligand for LRP1 to initiate post-receptor downstream signaling. the induction of replicative senescence downstream of p53 (Kortlever et al., 2006; Hiebert et al., 2018).”
BackgroundInfluentialSelf-citationMarote, A., Santos, D. J., Mendes-Pinheiro, B., Serre-Miranda, C., Anjo, S. I., Vieira, J., Ferreira-Antunes, F., Correia, J. S., Borges-Pereira, C., Pinho, A. G., et al. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10453-6 · Cited by 27
Nguyen, H. C., Bu, S., Nikfarjam, S., Rasheed, B., Michels, D., Singh, A., Singh, S., Marszal, C., McGuire, J. J., Feng, Q., et al. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.102921 · Cited by 29
“Activated SERPINE 1 also promotes cellular senescence downstream of the p53 regulatory network (105).”
BackgroundAsbestos: Modern Insights for Toxicology in the Era of Engineered Nanomaterials
Felley-Bosco, E., & MacFarlane, M. (2018) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00146 · Cited by 23
Angelini, F., Pagano, F., Bordin, A., Picchio, V., De Falco, E., & Chimenti, I. (2017) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2017.00062 · Cited by 25
“have demonstrated that p53, in association with SMAD3, is able to upregulate PAI-1 expression in aging mice and human fibroblasts, causing a downregulation of PI3K signaling and cyclin nuclear exclusion (89, 90) (Figure 1).”
BackgroundQiu, C., Wu, X., Bian, J., Ma, X., Zhang, G., Guo, Z., Wang, Y., Ci, Y., Wang, Q., Xiang, H., et al. (2020) · BMC Musculoskeletal Disorders · doi:10.1186/s12891-020-03329-8 · Cited by 24
Wang, K., Gong, Z., Chen, Y., Zhang, M., Wang, S., Yao, S., Liu, Z., Huang, Z., & Fei, B. (2023) · Clinical Epigenetics · doi:10.1186/s13148-023-01579-6 · Cited by 28
“Multiple stimuli that induce cellular senescence rely on p53 induction [12, 13].”
BackgroundUNC45A Confers Resistance to Histone Deacetylase Inhibitors and Retinoic Acid
Epping, M. T., Meijer, L. A. T., Bos, J. L., & Bernards, R. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-09-0187 · Cited by 25
“Quantitative reverse transcription-PCR assays were carried out to measure mRNA levels of genes using the 7500 Fast Real-Time PCR System as described (28).”
MethodSelf-citationKi, M., Kim, D. H., Abdelhamid, M. A. A., & Pack, S. P. (2025) · Biosensors · doi:10.3390/bios15110737 · Cited by 33
Xia, S., Ellis, L. V., Winkley, K., Menden, H. L., Mabry, S. M., Venkatraman, A., Louiselle, D. A., Gibson, M., Grundberg, E., Chen, J., et al. (2022) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00252.2022 · Cited by 30
Mdm2 exerts pro-apoptotic activities by antagonizing insulin-like growth factor-I-mediated survival
Froment, P., Dupont, J., & Marine, J. (2008) · Cell Cycle · doi:10.4161/cc.7.19.6807 · Cited by 25
Borlon, C., Godard, P., Eskes, C., Härtung, T., Zuang, V., & Toussaint, O. (2007) · Toxicology · doi:10.1016/j.tox.2007.08.096 · Cited by 24
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“Some studies have shown senescent cells have cancer-promoting functions, such as in tumors with p53 loss or mutation (27-30), while other studies have demonstrated that SASP is required to maintain senescence and can promote tumor regression (31-33).”
BackgroundLee, Y., Chang, W., Chang, C.-P., Liu, T., Chuang, C., Qian, K., Zheng, Y. G., & Li, C. (2019) · Scientific Reports · doi:10.1038/s41598-018-38394-6 · Cited by 24
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“When bound to tPA or uPA, PAI‐1 forms a complex that renders them catalytically inactive to inhibit the conversion of plasminogen to plasmin and hence dysregulate fibrinolysis and MMP activation.(6) VTN binding to PAI‐1 results in conformational changes to both proteins that lead to inhibition of VTN‐ integrin‐mediate…”
BackgroundInfluentialSeagle, B.-L. L., Yang, C. H., Eng, K. H., Dandapani, M., Odunsi-Akanji, O., Goldberg, G. L., Odunsi, K. O., Horwitz, S. B., & Shahabi, S. (2015) · Gynecologic Oncology · doi:10.1016/j.ygyno.2015.04.039 · Cited by 24
“Less transcription of P21, GADD45 and PAI-1 in HSM OCCs may result in decreased replicative senescence and decreased apoptosis of OCCs in response to cellular or genomic stress [29,34,35].”
BackgroundSenescence-Associated Alterations in Matrisome of Mesenchymal Stem Cells
Константиновна, М. Д., Kashirina, D. N., Ездакова, М. И., Larina, I., Buravkova, L. B., & Ratushnyy, A. Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105332 · Cited by 23
“It is important to note that PAI-1 is not just a biomarker of the aging phenotype, but is necessary and sufficient for the induction of replicative senescence upon the activation of p53 [79].”
BackgroundAging, Plasminogen Activator Inhibitor 1, Brain Cell Senescence, and Alzheimer's Disease.
Jiang, C., Rana, T., Jin, L., Farr, S. A., Morley, J. E., Qin, H., Liu, G., & Liu, R.-M. (2023) · PubMed Central · doi:10.14336/ad.2022.1220 · Cited by 23
“Increased PAI-1 has been used as a marker of cell senescence and has been shown to mediate cell senescence in vitro and in vivo [34, 42-47].”
BackgroundOta, K., Dohi, Y., Brydun, A., Nakanome, A., Ito, S., & Igarashi, K. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3574 · Cited by 23
“Both p21 and Pai1 have been identified as the genes associated with cellular senescence among the known p53 target genes, the former being an inhibitor of cyclin-dependent kinases, and the latter, an inhibitor of the PI(3)K-PKB-GSK3 b -cyclinD1-pRb pathway (19, 24).”
MLL Becomes Functional through Intra-Molecular Interaction Not by Proteolytic Processing
Yokoyama, A., Ficara, F., Murphy, M., Meisel, C., Hatanaka, C., Kitabayashi, I., & Cleary, M. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073649 · Cited by 24
“Consistent with these results, PAI-1 (also known as Serpine-1), a well-known senescence inducer [26], was highly expressed in dC homozygous MEFs, but expressed at normal levels in uc homozygous MEFs.”
ResultE6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts
Levav-Cohen, Y., Wolyniec, K., Alsheich-Bartok, O., Chan, A.-L., Woods, S. J., Jiang, Y.-H., Haupt, S., & Haupt, Y. (2011) · Oncogene · doi:10.1038/onc.2011.402 · Cited by 20
Bajpe, P. K., Heynen, G. J. J. E., Mittempergher, L., Grernrum, W., de Rink, I., Nijkamp, W., Beijersbergen, R. L., Bernards, R., & Huang, S. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01213-12 · Cited by 23
Self-citationNeault, M., Couteau, F., Bonneau, É., Guire, V. D., & Mallette, F. A. (2017) · International review of cytology · doi:10.1016/bs.ircmb.2017.04.001 · Cited by 23
Iscador Qu inhibits doxorubicin-induced senescence of MCF7 cells
Srdić‐Rajić, T., Santibanez, J. F., Kanjer, K., Miletić, N. T., Cavic, M. R., Galun, D., Jevric, M., Kardum, N., Konić‐Ristić, A., & Zoranovic, T. (2017) · Scientific Reports · doi:10.1038/s41598-017-03898-0 · Cited by 23
p53: from understanding its structure to advances in therapeutic targeting
Wang, W., Liu, X., Liu, H., Abolhassani, H., Yan, H., Zhang, H., & Wang, X. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02549-5 · Cited by 29
“67 Notably, the p53/p21 CIP1 and p16INK4a/Rb pathways are not independent but interact with each other through many crosstalk mechanisms.”
ERβ alters the chemosensitivity of luminal breast cancer cells by regulating p53 function
Bado, I., Pham, E., Soibam, B., Nikolos, F., Gustafsson, J.-Α., & Thomas, C. G. (2018) · Oncotarget · doi:10.18632/oncotarget.25147 · Cited by 23
Apremilast prevents IL‑17‑induced cellular senescence in ATDC5 chondrocytes mediated by SIRT1
Wang, B., Sun, W., Bi, K., Li, Y., & Li, F. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4845 · Cited by 25
“PAI‐1 is a member of the evolu‐ tionarily conserved serine protease inhibitor (SERPIN) family and is well known as a marker and mediator of senescence, revealed by its increased expression in senescent cells (34,35).”
BackgroundDonor and Recipient Age-Mismatches: The Potential of Transferring Senescence
Iske, J., Matsunaga, T., Zhou, H., & Tullius, S. G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.671479 · Cited by 22
Intersection of Inflammation and Senescence in the Aging Lung Stem Cell Niche
Allen, N. C., Reyes, N. S., Lee, J. Y., & Peng, T. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.932723 · Cited by 24
“Despite there being considerable heterogeneity among SASPs, one common feature is the ability of the SASP to induce local inflammation through mediators such as IL-6, IL-8, and PAI-1 (Kortlever et al., 2006; Salama et al., 2014).”
BackgroundSerpinE1 drives a cell-autonomous pathogenic signaling in Hutchinson–Gilford progeria syndrome
Catarinella, G., Nicoletti, C., Bracaglia, A., Procopio, P., Salvatori, I., Taggi, M., Valle, C., Ferri, A., Canipari, R., Puri, P., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05168-y · Cited by 23
“Conversely, lower SerpinE1 levels have been linked to protection against physiological aging [31, 32] and SerpinE1 deficiency overcome senescence [33].”
BackgroundVizioli, M. G., Santos, J. D., Pilotti, S., Mazzoni, M., Anania, M. C., Miranda, C., Pagliardini, S., Pierotti, M. A., Gil, J., & Greco, A. (2014) · Oncotarget · doi:10.18632/oncotarget.2013 · Cited by 23
“In addition to classical senescence players like p16INK4a, p21CIP1 and p53, a complex cocktail of factors including proinflammatory cytokines, chemokines, extracellular proteases, matrix components and growth factors, regulates the initiation and maintenance of senescence [25-28].”
BackgroundSimone, T. M., & Higgins, P. J. (2015) · Journal of Developmental Biology · doi:10.3390/jdb3010011 · Cited by 25
“In some instances, sustained PAI-1 expression, particularly in the context of p53 modulation, may activate a cellular senescence program [36].”
BackgroundSelf-citationRuan, X., Zuo, Q., Jia, H., Chau, J. F. L., Lin, J., Ao, J., Xia, X., Liu, H., Habib, S. L., Fu, C., et al. (2015) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjv015 · Cited by 22
“Smad2/3 can interact with p53 to induce the expression of target genes such as p21Cip1 to inhibit cell proliferation (Cordenonsi et al., 2003; Kortlever et al., 2006; Shirai et al., 2011; Samarakoon et al., 2013; Overstreet et al., 2014).”
BackgroundConstitutive and induced functions of the p53 gene
Zheltukhin, A. O., & Chumakov, P. M. (2010) · Biochemistry (Moscow) · doi:10.1134/s0006297910130110 · Cited by 23
Liu, S., Fang, X., Hall, H. S., Yu, S., Smith, D. L., Lu, Z., Fang, D., Liu, J., Stephens, L. C., Woodgett, J. R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704242105 · Cited by 23
The Dynamic Process and Its Dual Effects on Tumors of Therapy-Induced Senescence
Liao, C., Xiao, Y., & Liu, L. (2020) · Cancer Management and Research · doi:10.2147/cmar.s285083 · Cited by 24
“PAI-1 was also found to be essential for the induction of senescence even in the absence of p53.(60) In other studies, senescent MCF-7 breast cancer cells triggered by adriamycin were observed to have an antiproliferative effect in which they induced a senescent state of cell cycle arrest in naive MCF-7 cells by secre…”
BackgroundWesolowski, S. R., Purup, S., Vestergaard, M., Sejrsen, K., Meyer, M. J., Amburgh, M. V., & Boisclair, Y. R. (2007) · Journal of Endocrinology · doi:10.1677/joe-07-0501 · Cited by 22
“2006, Kortlever et al .”
PAI-1: A New Target for Controlling Lung-Cell Senescence and Fibrosis?
Adnot, S., Breau, M., & Houssaini, A. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0341ed · Cited by 25
“The fact that PAI-1 can serve as both a marker and a promoter of cell senescence was initially demonstrated by Kortlever and colleagues in vitro (10).”
BackgroundLin, Y., Kuo, T.-T., Lo, C.-C., Cheng, W., Chang, W., Tseng, G.-C., Bai, S.-T., Huang, Y., Hsieh, C.-Y., Hsu, H., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.65488 · Cited by 21
“Given that a typical rapid decline in PAI-1 levels was detected prior to the onset of DNA synthesis [43] and PAI-1 reduction leading to escape from senescenceassociated proliferative arrest in primary fibroblasts [44], PAI-1 may have a negative influence on cell growth.”
BackgroundMaru, Y. (2021) · Springer eBooks · doi:10.1007/978-981-16-1757-7_11 · Cited by 25
HdmX overexpression inhibits oncogene induced cellular senescence
Miller, K. R., Kelley, K. D., Tuttle, R., & Berberich, S. J. (2010) · Cell Cycle · doi:10.4161/cc.9.16.12779 · Cited by 21
“Reduction of HdmX protein levels in LNCaP cells (high HdmX, mutant Ras, wild-type p53) led to an increase in irreversibly b-galactosidase positive cells and an increase in PAI-1, a senescence associated p53 target gene.(13) These findings demonstrate that release of p53 by inhibition of HdmX can trigger senescence in…”
BackgroundUne re-vue de la sénescence cellulaire
Bischof, O., Dejean, A., & Pineau, P. (2009) · médecine/sciences · doi:10.1051/medsci/2009252153 · Cited by 30
Transcriptome analysis and tumor suppressor requirements of STAT5‐induced senescence
Mallette, F. A., Moiseeva, O. V., Calabrese, V., Mao, B., Gaumont‐Leclerc, M., & Ferbeyre, G. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05192.x · Cited by 21
“INHBA Inhibin A +2,1 GMFB Glial maturation factor beta +2, 9 TIMP3 Tissue inhibitor of metalloproteinase 3 +2, 1 Serpines Serpin B2 +3, 4 Serpine E1 (PAI-1) +2, 0 + (20, 56) Serpine E2 +3, 3 TNFRSF11B Tumor necrosis factor receptor superfamily 11B/osteoprotegerin +6, 8”
BackgroundZhang, B., Zhang, F., Lu, F., Wang, J., Zhou, W., Wang, H. H., & Yu, B. (2022) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2101024 · Cited by 21
“As previously de‐ scribed, SERPINE1 is involved in cellular and replica‐ tive senescence (Kortlever et al., 2006).”
BackgroundChronic Infections: A Possible Scenario for Autophagy and Senescence Cross-Talk
Aguilera, M. O., Delgui, L. R., Romano, P. S., & Colombo, M. I. (2018) · Cells · doi:10.3390/cells7100162 · Cited by 20
“are used as markers of senescence [53].”
BackgroundFetuin-A: A Major Fetal Serum Protein that Promotes “Wound Closure” and Scarless Healing
Wang, X., Hayes, M. T., Kempf, M., Fraser, J. F., Liu, P.-Y., Cuttle, L., Friend, L., Rothnagel, J. A., Saunders, N. A., & Kimble, R. M. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701119 · Cited by 20
Chan, J. M., Ho, S. H. Y., & Tai, I. T. (2010) · Carcinogenesis · doi:10.1093/carcin/bgq034 · Cited by 20
Ratushnyy, A. Y., Lobanova, M. V., & Buravkova, L. B. (2017) · Cell Biochemistry and Function · doi:10.1002/cbf.3267 · Cited by 20
“SERPINE1 is another highly expressed gene in “senescent” cells.(67) Its product is”
BackgroundPhosphorylation of SOCS1 Inhibits the SOCS1–p53 Tumor Suppressor Axis
Saint‐Germain, E., Mignacca, L., Huot, G., Acevedo, M., Moineau‐Vallée, K., Calabrese, V., Bourdeau, V., Rowell, M., Ilangumaran, S., Lessard, F., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-1503 · Cited by 19
“GST GST 1 67 98 303 323 363 393 p53 FL (1-393) GST”
BackgroundLupu‐Meiri, M., Geras‐Raaka, E., Lupu, R., Shapira, H., Sandbank, J., Segal, L., Gershengorn, M. C., & Oron, Y. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24068 · Cited by 19
“…has been used to show that PAI-1 is involved in the induction of ‘‘replicative senescence’’ by p53 in mouse embryo fibroblasts and human BJ fibroblasts (Kortlever et al., 2006) and in the signaling activity of transforming growth factor-b in human *Correspondence to: Yoram Oron, Department of…”
MethodKalouche, G., Boucher, C., Coste, A., Debüssche, L., Orsini, C., Baudouin, C., Debeir, T., Vigé, X., & Rostène, W. H. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.06.008 · Cited by 19
“induction of senescence [55], are down-regulated by an EP2 receptor agonist, suggesting that EP2 activation could be an interesting mechanism in preventing TM senescence.”
BackgroundThe Importance of Cellular Senescence in Frailty and Cardiovascular Diseases
Boccardi, V., & Mecocci, P. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-33330-0_9 · Cited by 19
Stress-induced cellular senescence contributes to chronic inflammation and cancer progression.
KOBASHIGAWA, S., M. SAKAGUCHI, Y., MASUNAGA, S., & MORI, E. (2019) · Thermal Medicine · doi:10.3191/thermalmed.35.41 · Cited by 18
Molecular turnover, the H3.3 dilemma and organismal aging (hypothesis)
Saade, E., Pirozhkova, I., Aimbetov, R., Lipinski, M., & Ogryzko, V. V. (2015) · Aging Cell · doi:10.1111/acel.12332 · Cited by 22
“The SMS includes IGFBP, PAI-1, TGFb1 (Tremain et al., 2000; Kortlever et al., 2006; Wajapeyee et al., 2008), and immune regulators such as IL6, IL6R, IL8, CXCL1, 5, and 7 (Shelton et al., 1999; de Magalhaes et al., 2004; Xue et al., 2007; Acosta et al., 2008; Kuilman et al., 2008), and secretion of…”
BackgroundLive-Cell Mesothelioma Biobank to Explore Mechanisms of Tumor Progression
Oehl, K., Kresoja‐Rakic, J., Opitz, I., Vrugt, B., Weder, W., Stahel, R. A., Wild, P. J., & Felley‐Bosco, E. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00040 · Cited by 19
Biomarkers of senescence in non-human primate adipose depots relate to aging
Kavanagh, K., Sherrill, C., Ruggiero, A. D., Block, M. R., Vemuri, R., Davis, M., & Olivier, A. (2020) · GeroScience · doi:10.1007/s11357-020-00230-z · Cited by 17
Phosphate and Cellular Senescence
Hu, M. C., & Moe, O. W. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-91623-7_7 · Cited by 18
Transcription activity is required for p53-dependent tumor suppression
Gaidarenko, O., & Xu, Y. (2009) · Oncogene · doi:10.1038/onc.2009.290 · Cited by 17
“Plasminogen activator inhibitor-1 is required for p53dependent replicative senescence (Kortlever et al., 2006). p53 can induce the differentiation of embryonic stem cells after DNA damage by directly suppressing the expression of Nanog, which is required for the selfrenewal of embryonic stem cells…”
Gunaratna, R. T., Santos, A., Luo, L., Nagi, C. S., Lambertz, I. U., Spier, M. E., Conti, C. J., & Fuchs‐Young, R. (2019) · Oncogene · doi:10.1038/s41388-018-0630-4 · Cited by 18
Role of plasminogen activator inhibitor-1 (PAI-1) in age-related cardiovascular pathophysiology
Khoddam, A., Vaughan, D. E., & Wilsbacher, L. D. (2025) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2024.38 · Cited by 15
“Mechanistically, early reports showed that PAI-1 overexpression induced senescence in p53-deficient fibroblasts, indicating PAI-1 signals independently of p53 [55] .”
Patel, S. K., Bons, J., Rose, J., Chappel, J. R., Beres, R. L., Watson, M. A., Webster, C. M., Burton, J. B., Bruderer, R., Desprez, P. Y., et al. (2025) · Aging · doi:10.18632/aging.206292 · Cited by 18
“Notable secondary signals include integrin alpha-4 [40], SERPINE1 [41, 42], insulin-like growth factor-binding protein 7 [43, 44], transforming growth factor beta-1 proprotein [45], SPARC [46], and hexceramides (HexCer) [30].”
p53 as the main traffic controller of the cell signaling network
Sebastian, S. (2010) · Frontiers in bioscience · doi:10.2741/3669 · Cited by 16
RBM4 regulates cellular senescence via miR1244/SERPINE1 axis
Wang, L., Zhang, X., Sheng, J., Chen, L., Zhi, L., Zheng, Q., Qi, Y., Wang, L., Zhang, J., Zhao, J., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05563-z · Cited by 16
“In addition to regulating fibrinolysis, SERPINE1 also directly contributes to cellular senescence [24].”
BackgroundThe Regulation of Cellular Senescence in Cancer
Zhang, X., Gao, Y., Zhang, S., Wang, Y., Du, Y., Hao, S., & Ni, T. (2025) · Biomolecules · doi:10.3390/biom15030448 · Cited by 17
“A thorough understanding of the interplay between cellular senescence and cancer cells is essential for e ff ective cancer treatment and prevention (”
Enhancing the Function of CD34+ Cells by Targeting Plasminogen Activator Inhibitor-1
Hazra, S., Stepps, V., Bhatwadekar, A. D., Caballero, S., Boulton, M. E., Higgins, P. J., Nikonova, E. V., Pepine, C. J., Thut, C. J., Finney, E. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079067 · Cited by 16
“To this end, recent data confirms the role of one such TGF-β1-regulated gene, PAI-1 (SERPINE1), as an important mediator of cellular growth arrest [13].”
BackgroundSelf-citationThe Pro/Pro genotype of the p53 codon 72 polymorphism modulates PAI-1 plasma levels in ageing
Testa, R., Bonfigli, A. R., Salvioli, S., Invidia, L., Pierini, M., Sirolla, C., Marra, M., Testa, I., Fazioli, F., Recchioni, R., et al. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.06.001 · Cited by 16
Molecular mechanisms of cellular senescence and immortalization of human cells
Kiyono, T. (2007) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.11.12.1623 · Cited by 16
“As a p53 downstream target, PAI-1, can also inhibit the PI3K/Akt pathway and induce senescence in the absence of p53 [27] , PAI-1 might be involved in negative feedback loops.”
BackgroundLucas, J. H., Wang, Q., Muthumalage, T., & Rahman, I. (2021) · Toxics · doi:10.3390/toxics9060144 · Cited by 16
“Fibroblast deficient in PAI-1 are resistant to cellular senescence [31] and knockdown of PAI-1 blunts TGF-β induced senescence [32].”
BackgroundAge-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps
Jo, A., Choi, T. G., Han, J. Y., Tabor, M. H., Kolliputi, N., Lockey, R. F., & Cho, S. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.845324 · Cited by 15
Targeting NRF2 to promote epithelial repair
Hiebert, P., & Werner, S. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220228 · Cited by 16
Engineered Aging Cardiac Tissue Chip Model for Studying Cardiovascular Disease
Budhathoki, S., Graham, C., Sethu, P., & Kannappan, R. (2021) · Cells Tissues Organs · doi:10.1159/000516954 · Cited by 15
“…expression of cell cycle inhibitors like p26, p21, and p53, growth factors like TGFΒ, expression of the senescence-associated marker p16INK4a, accumulation of reactive oxygen species (ROS) [Kortlever et al., 2006, 2008; Elzi et al., 2012; Malaquin et al., 2015; Kannappan et al., 2017, 2019].”
BackgroundNian, S., Mi, Y., Ren, K., Wang, S., Li, M., & Yang, D. (2022) · Human Cell · doi:10.1007/s13577-022-00703-7 · Cited by 15
“In addition, PAI-1 also plays a necessary and sufficient role in the replicative senescence of mouse fibroblasts, and PAI-1 knockout MFF cells can induce immortalization [29].”
BackgroundCarnitine palmitoyltransferase 1C contributes to progressive cellular senescence
Wang, Y., Yu, T., Zhou, Y., Wang, S., Zhou, X., Wang, L., Ou, T., Chen, Y., Zhou, Y., Zhang, H., et al. (2020) · Aging · doi:10.18632/aging.103033 · Cited by 15
Role of non-cardiomyocytes in anticancer drug-induced cardiotoxicity: A systematic review
Xie, S., Yang, Y., Luo, Z., Li, X., Liu, J., Zhang, B., & Li, W. (2022) · iScience · doi:10.1016/j.isci.2022.105283 · Cited by 14
“It may be acute, occurring within 2–3 days or delayed until 10 to 15 years after chemotherapy (Kortlever et al., 2006; Ghosh and Vaughan, 2012; Ghosh et al., 2010; Ando and Yamamoto, 2013).”
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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