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AP-1 imprints a reversible transcriptional programme of senescent cells.
Open accessAbstract
Senescent cells affect many physiological and pathophysiological processes. While select genetic and epigenetic elements for senescence induction have been identified, the dynamics, epigenetic mechanisms and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding the deliberate therapeutic targeting of senescence for health benefits. Here, we examined the possibility that the epigenetic state of enhancers determines senescent cell fate. We explored this by generating time-resolved transcriptomes and epigenome profiles during oncogenic RAS-induced senescence and validating central findings in different cell biology and disease models of senescence. Through integrative analysis and functional validation, we reveal links between enhancer chromatin, transcription factor recruitment and senescence competence. We demonstrate that activator protein 1 (AP-1) 'pioneers' the senescence enhancer landscape and defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells. Together, our findings enabled us to manipulate the senescence phenotype with potential therapeutic implications.
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“This temporal regulation of senescence- associated phenotypes seems to be, at least in part, controlled by the sequential and dynamic activation of diverse transcriptional programmes and hierarchies 72-74 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [74]
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“Indeed, senescence- associated phenotypes are temporal and early- stage senescent cells are phenotypically different from late- stage senescent cells 72-74 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [74]
In the citing paper
“They demonstrated that a hierarchical transcription factor network defines the senescence transcriptional program and identified activator protein 1 (AP-1) as a master regulator that drives the transcriptional program of senescent cells thereby revealing promising pathways with therapeutic implications for modulation of senescence in vivo.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Martínez-Zamudio et al., 2020
In the citing paper
“They demonstrated that a hierarchical transcription factor network defines the senescence transcriptional program and identified activator protein 1 (AP-1) as a master regulator that drives the transcriptional program of senescent cells thereby revealing promising pathways with therapeutic implications for modulation of senescence in vivo.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Martínez-Zamudio et al., 2020
In the citing paper
“A recent study by Martínez-Zamudio et al. (2020), revealed links between enhancer chromatin, transcription factor recruitment, and senescence competence.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Martínez-Zamudio et al., 2020
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The senescence-associated secretory phenotype and its physiological and pathological implications
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Goel, S., Bergholz, J. S., & Zhao, J. J. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00456-3 · Cited by 565
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Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
Prasanna, P. G. S., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., Xi, D., Zheng, G., van Deursen, J., Goronzy, J. J., et al. (2021) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djab064 · Cited by 359
“There is now evidence for metabolic (47) and stem cell-like remodeling (20,48) among SnCs and for the presence of an immunogenic switch that renders SnCs susceptible to an adaptive T-cell attack (49).”
BackgroundSelf-citationA blood atlas of COVID-19 defines hallmarks of disease severity and specificity
Ahern, D. J., Ai, Z., Ainsworth, M., Allan, C., Allcock, A., Angus, B., Ansari, M. A., Arancibia-Cárcamo, C. V., Aschenbrenner, D., Attar, M., et al. (2022) · Cell · doi:10.1016/j.cell.2022.01.012 · Cited by 328
“AP-1 is a pioneer transcription factor that reversibly imprints the senescence enhancer landscape following stress and can be modulated to reverse T cell exhaustion (Lynn et al., 2019; Martı́nez-Zamudio et al., 2020).”
BackgroundMesenchymal Stem/Stromal Cell Senescence: Hallmarks, Mechanisms, and Combating Strategies
Weng, Z., Wang, Y., Ouchi, T., Liu, H., Qiao, X., Wu, C., Zhao, Z., Li, L., & Li, B. (2022) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szac004 · Cited by 303
Gerhardt, L. M. S., Liu, J., Koppitch, K. A., Cippà, P. E., & McMahon, A. P. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2026684118 · Cited by 237
Martínez‐Zamudio, R. I., Dewald, H. K., Vasilopoulos, T., Gittens‐Williams, L., Fitzgerald‐Bocarsly, P., & Herbig, U. (2021) · Aging Cell · doi:10.1111/acel.13344 · Cited by 213
“Similarly, senescent- like CD8+ TEMRA, CD57, or KLRG1 expressing lymphocytes also increasingly develop with age in humans (Callender et al., 2020; Merino et al., 1998; Ouyang et al., 2003; Saule et al., 2006), albeit at significantly lower levels compared to the total SA- βGal expressing CD8+ T…”
BackgroundSelf-citationCellular adaptation to cancer therapy along a resistance continuum
França, G. S., Baron, M., King, B. R., Bossowski, J. P., Bjornberg, A., Pour, M., Rao, A. N., Patel, A. S., Misirlioğlu, S., Barkley, D., et al. (2024) · Nature · doi:10.1038/s41586-024-07690-9 · Cited by 235
“A possible mechanism is that promiscuous AP1 binding ‘pioneers’ the enhancer landscape, which is potentiated by recurrent stress stimuli 28,29 , thus establishing and maintaining a cellular memory upon continuous stress 30 .”
The Cancer SENESCopedia: A delineation of cancer cell senescence
Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., Wang, L., Schepers, A., Wang, C., Jin, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109441 · Cited by 201
Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
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COVID-19 and cellular senescence
Schmitt, C. A., Tchkonia, T., Niedernhofer, L. J., Robbins, P. D., Kirkland, J. L., & Lee, S. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-022-00785-2 · Cited by 153
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“Consistent with this, recent studies have demonstrated that AP-1 drives chromatin accessibility and enhancer activation in benign senescent cells [58, 59].”
BackgroundINX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors
Dietrich, C. A., Trub, A. G., Ahn, A., Taylor, M., Ambani, K., Chan, K. T., Lu, K., Mahendra, C. A., Blyth, C., Coulson, R. S., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0954 · Cited by 142
“Given the critical role of chromatin remodeling in governing the senescence phenotype (29, 30, 37), we performed the Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-seq) on (i) parental cells treated with control vehicle or abemaciclib; (ii) abemaciclib-and abemaciclib/…”
Senescent glia link mitochondrial dysfunction and lipid accumulation
Byrns, C. N., Perlegos, A. E., Miller, K. N., Jin, Z., Carranza, F. R., Manchandra, P., Beveridge, C. H., Randolph, C. E., Chaluvadi, V. S., Zhang, S., et al. (2024) · Nature · doi:10.1038/s41586-024-07516-8 · Cited by 147
“Using Activator protein 1 (AP1) activity to screen for senescence 14,15 , we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction.”
Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer
Troiani, M., Colucci, M., D’Ambrosio, M., Guccini, I., Pasquini, E., Varesi, A., Valdata, A., Mosole, S., Revandkar, A., Attanasio, G., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29824-1 · Cited by 134
“Among genes involved in transcriptional regulation, we found c-Jun , a pioneer transcription factor recently described as a master regulator of senescence, and additional genes encoding proteins that heterodimerize with c-Jun to form AP-1 complex, such as c-Fos and Atf3 26 (Fig.”
The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging
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Cellular senescence: Neither irreversible nor reversible
Reimann, M., Lee, S., & Schmitt, C. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232136 · Cited by 125
“Recently, extensive epigenomic profiling identified AP-1 TF as top-hierarchy pioneers that interact with enhancers in an OIS-typical manner (Mart´ ı nez-Zamudio et al., 2020).”
BackgroundSelf-citationParamos-de-Carvalho, D., Jacinto, A., & Saúde, L. (2021) · eLife · doi:10.7554/elife.72449 · Cited by 111
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“, SERPINE1 in replicative senescence [52], ETS2 in oncogene stress [53], CYR61/CCN1 in wound healing [54], FOS in enhancer organization [55], ZFP36 in mRNA stability regulation [56], and ING1 in epigenetic regulation [57]) (Fig.”
BackgroundChromatin basis of the senescence-associated secretory phenotype
Hao, X., Wang, C., & Zhang, R. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.12.003 · Cited by 94
Selective remodelling of the adipose niche in obesity and weight loss
Miranda, A. M. A., McAllan, L., Mazzei, G., Andrew, I., Davies, I., Ertuğrul, M. S., Kenkre, J. S., Kudo, H., Carrelha, J., Patel, B., et al. (2025) · Nature · doi:10.1038/s41586-025-09233-2 · Cited by 112
“…implicated in cell cycle arrest; TFs that control ciliogenesis ( RFX2/RFX3 ), which is a putative senescence regulator; orphan nuclear receptor TFs that are induced by DNA damage and oxidative stress, key senescence triggers; and multiple candidate TFs not previously linked to senescence 36–40 .”
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ATF3 drives senescence by reconstructing accessible chromatin profiles
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“When our project was about to be completed, we found that Ricardo et al.(Martinez-Zamudio et al., 2020) recently published research on the regulation of AP-1 transcription factors to senescence program and our work can confirm and complement each other.”
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“Remarkably, depletion of the AP-1 superfamily member c-Jun alone is adequate to partially reverse the cell cycle arrest 57 .”
BackgroundInfluentialTighanimine, K., de Freitas, J. A. N. L. F., Nemazanyy, I., Bankolé, A., Benarroch, D., Brodesser, S., Doré, G. R. G., Robinson, L. J., Bénit, P., Ladraa, S., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-023-00972-y · Cited by 80
“No statistical method was used to predetermine the sample size, but our sample sizes are similar to those reported in a previous publication 20 .”
InfluentialSelf-citationGiroud, J., Bouriez, I., Paulus, H., Pourtier, A., Debacq‐Chainiaux, F., & Pluquet, O. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310788 · Cited by 87
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CDK4/6 Inhibitors in Combination Therapies: Better in Company Than Alone: A Mini Review
Vinciguerra, G. L. R., Sonego, M., Segatto, I., Dall’Acqua, A., Vecchione, A. M., Baldassarre, G., & Belletti, B. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891580 · Cited by 73
“On one hand, AP-1 is responsible for the activation of therapy-induced senescence program in neoplastic cells that, as we discussed above, represents one of the main consequences of Palbociclib administration (101).”
BackgroundTGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state
Matsuda, S., Revandkar, A., Dubash, T. D., Ravi, A., Wittner, B. S., Lin, M., Morris, R. T., Burr, R., Guo, H., Seeger, K., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112129 · Cited by 76
“21 Analysis of published transcriptomic data following oncogenic Ras-OIS of human lung fibroblasts 47 showed a gradual decline in activator E2Fs (E2F1 and E2F3) ( p = 0.0023 ; Figure 2E) and E2F targets ( p < 2.2e − 16 ; Figure 2F) as cells progress toward senescence.”
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“b 91 HDAC4-bound and regulated SES were ordered according to the reported binding by AP-1 [9] (red squares), BRD4 [4] (blue squares), or both (violet squares) during senescence.”
BackgroundMethodAP ‐1 is a regulatory transcription factor of inflammaging in the murine kidney and liver
Yu, X., Wang, Y., Song, Y., Gao, X., & Deng, H. (2023) · Aging Cell · doi:10.1111/acel.13858 · Cited by 63
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“AP-1 has previously been implicated with senescence induction 35 and we observed JUN directly binding to an enhancer element in the CDKN1A gene 20 kb upstream of the transcription start site (TSS) which is predominantly accessible in in fl ammatory PT cells, while the remaining regulatory elements…”
Irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation
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Dynamic 3D genome reorganization during senescence: defining cell states through chromatin
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“Thesedynamic characteristics of senescence gene expression are of course linked to chromatin states [51].”
InfluentialCellular senescence in the tumor microenvironment and context‐specific cancer treatment strategies
Yasuda, T., Baba, H., & Ishimoto, T. (2021) · FEBS Journal · doi:10.1111/febs.16231 · Cited by 53
Wang, Y., Liu, L., Song, Y., Yu, X., & Deng, H. (2022) · Protein & Cell · doi:10.1007/s13238-021-00894-z · Cited by 50
“Recently, AP-1 family transcription factors were found to play an important role in regulating the senescence program, and knockdown of AP-1 was found to attenuate part of senescence phenotypes (Martínez-Zamudio et al., 2020; Zhang et al., 2021), which highlights the regulatory roles of TFs in RS.”
InfluentialAP-1 activation mediates post-natal cardiomyocyte maturation
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Schwab, N., Taskina, D., Leung, E., Innes, B. T., Bader, G. D., & Hazrati, L. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1027116 · Cited by 56
Glial AP1 is activated with aging and accelerated by traumatic brain injury
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Li, Y., Li, C., Zhou, Q., Liu, X., Qiao, Y., Xie, T., Sun, H., Ong, M. T., & Wang, H. (2025) · Nature Communications · doi:10.1038/s41467-025-61403-y · Cited by 58
“Considering AP-1 TFs have been noticed as a pos-sibleregulatorofsenescencestateinmultiplecells/tissues 49 – 54 ,wethus reason targeting JUNB or other AP-1 TFs could be a powerful seno-morphic approach that is worth further investigation in the future.”
Subcellular structure, heterogeneity, and plasticity of senescent cells
Bitencourt, T. C., Vargas, J. E., Silva, A. O., Fraga, L. R., & Filippi‐Chiela, E. C. (2024) · Aging Cell · doi:10.1111/acel.14154 · Cited by 46
“Potential players mediating the transcriptional heterogeneity of SnCs include the AP-1 transcription factor (Martínez-Zamudio et al., 2020) and the H3-specific demethylase KDM4 (Zhang et al., 2021).”
BackgroundBenítez, S., Cordero, A., Santamaría, P. G., Redondo-Pedraza, J., Rocha, A. S., Collado-Solé, A., Jimenez, M., Sanz-Moreno, A., Yoldi, G., Santos, J. C., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.04.022 · Cited by 41
“The reversibility of senescence has been a subject of debate (Martı́nez-Zamudio et al., 2020).”
BackgroundEscape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars
Martínez‐Zamudio, R. I., Stefa, A., de Freitas, J. A. N. L. F., Vasilopoulos, T., Simpson, M., Doré, G. R. G., Roux, P., Galan, M. A., Chokshi, R. J., Bischof, O., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100293 · Cited by 47
Self-citationShetty, A., Tripathi, S. K., Junttila, S., Buchacher, T., Biradar, R., Bhosale, S. D., Envall, T., Laiho, A., Moulder, R., Rasool, O., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac256 · Cited by 46
“Genomic co-occupancy is a distinguished feature of FOS, JUN and ATF family members (2,79,107).”
Integrated multi-omics approach revealed cellular senescence landscape
Song, Q., Hou, Y., Zhang, Y., Liu, J., Wang, Y., Fu, J., Zhang, C., Cao, M., Cui, Y., Zhang, X., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac885 · Cited by 44
Redmer, T., Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtová, K., Kodajova, P., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02022-x · Cited by 39
“Our results support a previous study where JUN depletion was linked to diminished inflammatory responses and reverting the senescent/SASP phenotype of RAS-OIS fibroblasts to a proliferating phenotype [23].”
BackgroundResultInfluentialSpurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging
Sen, P., Donahue, G., Li, C. Y., Egervári, G., Yang, N., Lan, Y., Robertson, N., Shah, P. P., Kerkhoven, E., Schultz, D., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00384-3 · Cited by 39
Autophagy inhibition signals through senescence to promote tumor suppression
Peng, N., Kang, H. H., Feng, Y., Minikes, A. M., & Jiang, X. (2022) · Autophagy · doi:10.1080/15548627.2022.2155794 · Cited by 37
Early growth response 2 (EGR2) is a novel regulator of the senescence programme
Tyler, E. J., del Arroyo, A. G., Wallis, R., Hughes, B., Garbe, J. C., Stampfer, M. R., Koh, J., Lowe, R., Philpott, M. P., & Bishop, C. L. (2021) · Aging Cell · doi:10.1111/acel.13318 · Cited by 34
Fernández-Duran, I., Quintanilla, A., Tarrats, N., Birch, J., Hari, P., Millar, F. R., Lagnado, A. B., Smer-Barreto, V., Muir, M., Brunton, V. G., et al. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00917-6 · Cited by 35
“Interestingly, the specific time point where caspase-4 is assembled coincides with the moment of transition to a proinflammatory, NF-κB -dependent SASP in OIS [32, 33].”
BackgroundGiorgio, E. D., Ranzino, L., Tolotto, V., Dalla, E., Burelli, M., Gualandi, N., & Brancolini, C. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06548-2 · Cited by 32
“This reorganization involves the restructuring of proximal and distal regulatory elements (promoters and enhancers) with the stabilization of new super-enhancers (SEs) [7 – 9].”
Early response evaluation by single cell signaling profiling in acute myeloid leukemia
Tislevoll, B. S., Hellesøy, M., Fagerholt, O. H. E., Gullaksen, S., Srivastava, A., Birkeland, E., Kleftogiannis, D., Durán, P. A., Piechaczyk, L., Tadele, D. S., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35624-4 · Cited by 33
Netterfield, T. S., Ostheimer, G. J., Tentner, A. R., Joughin, B. A., Dakoyannis, A. M., Sharma, C. D., Sorger, P. K., Janes, K. A., Lauffenburger, D. A., & Yaffe, M. B. (2022) · Cell Systems · doi:10.1016/j.cels.2023.06.005 · Cited by 32
Yu, D., Yang, P., Lu, X., Huang, S., Liu, L., & Fan, X. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01184-3 · Cited by 31
“7C), which are associated with senescence [71].”
Beyond cell cycle regulation: The pleiotropic function of CDK4 in cancer
Ziegler, D. V., Parashar, K., & Fajas, L. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.12.002 · Cited by 32
“In this RB-dependent fashion, CDK4/6 inhibition reprograms the enhancer landscape by stimulating AP-1 transcriptional activity [133], which constitutes a canonical transcriptional program in senescent cells [83].”
BackgroundRising from the ashes: cellular senescence in regeneration
Walters, H., & Yun, M. H. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.06.002 · Cited by 30
Biomarkers of Aging and Relevant Evaluation Techniques: A Comprehensive Review
Xue, T., Zhu, Z., Wang, L., Li, C., Sun, L., Wang, W., & Gong, W. (2023) · Aging and Disease · doi:10.14336/ad.2023.00808-1 · Cited by 37
“High SA-β-gal CD8 + cells, however, displayed a T-cell destiny that was distinct from that of T cells that were previously classified as senescent [104].”
BackgroundWang, H., Yu, Y., Li, R., Zhang, H., Chen, Z., Sun, C., & Zhuang, J. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.022 · Cited by 36
“Consequently, the integration of mathematical modeling with multi-omics technologies has emerged as a powerful tool for understanding and predicting the temporal evolution of SASP 82 .”
HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications
Cuttini, E., Goi, C., Pellarin, E., Vida, R., & Brancolini, C. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1116660 · Cited by 28
“Interestingly, several of these SEs that control senescence are activated by the AP-1 TFs, in complex with the HAT p300/KAT3B (Martínez-Zamudio et al., 2020).”
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Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells
Shetty, A., Bhosale, S. D., Tripathi, S. K., Buchacher, T., Biradar, R., Rasool, O., Moulder, R., Galande, S., & Lahesmaa, R. (2021) · ACS Omega · doi:10.1021/acsomega.1c03681 · Cited by 25
A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells
Baird, L., Taguchi, K., Zhang, A., Takahashi, Y., Suzuki, T., Kensler, T. W., & Yamamoto, M. P. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102845 · Cited by 28
“Through the time-course-dependent evaluation of gene enhancer activity, senescence priming has recently been ascribed to the AP-1 transcription factor, which has been labelled a “senescence pioneer” due to its ability to imprint a reversible transcriptional program onto senescent cells [29].”
BackgroundOzdemir, S. A., Faizan, M. I., Kaur, G., Shaikh, S. B., Islam, K. U., & Rahman, I. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199687 · Cited by 28
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Neutrophil-activating secretome characterizes palbociclib-induced senescence of breast cancer cells
Favaretto, G., Rossi, M. N., Cuollo, L., Laffranchi, M., Cervelli, M., Soriani, A., Sozzani, S., Santoni, A., & Antonangeli, F. (2024) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-024-03695-5 · Cited by 25
Giorgio, E. D., Dalla, E., Tolotto, V., D’Este, F., Paluvai, H., Ranzino, L., & Brancolini, C. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae501 · Cited by 26
“During senescence, selected TEs and SEs are activated to orchestrate the transcription of the senescence program ( 9 , 11 , 12 ).”
BackgroundSMARCA4 regulates the NK-mediated killing of senescent cells
Reen, V., D’Ambrosio, M., Søgaard, P. P., Tyson, K., Leeke, B. J., Clément, I., Dye, I. C., Pombo, J., Kuba, A., Lan, Y., et al. (2025) · Science Advances · doi:10.1126/sciadv.adn2811 · Cited by 26
“Last, transcription factor motif enrichment analysis suggested that activator protein 1 (AP-1), which is known to control super-enhancers during senescence ( 50 ), is a master regulator of the process (fig.”
Self-citationTransposable element 5mC methylation state of blood cells predicts age and disease
Morandini, F., Lu, J. Y., Rechsteiner, C., Shadyab, A. H., Casanova, R., Snively, B. M., Seluanov, A., & Gorbunova, V. A. (2024) · Nature Aging · doi:10.1038/s43587-024-00757-2 · Cited by 28
“A notable number of TFs were members of the AP-1 complex (JUN–BATF– FOSL1), which initiates the senescence program and upregulates part of the senescence-associated secretory phenotype 58,59 .”
Pietrogrande, G., Shaker, M. R., Stednitz, S. J., Soheilmoghaddam, M., Aguado, J., Morrison, S. D., Zambrano, S., Tabassum, T., Javed, I., Cooper-White, J. J., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02732-0 · Cited by 23
“Open Access funding enabled and organized by CAUL and its Member Institutions.”
The Evolving Pathways of the Efficacy of and Resistance to CDK4/6 Inhibitors in Breast Cancer
Gomes, I., Abreu, C., Costa, L., & Casimiro, S. (2023) · Cancers · doi:10.3390/cancers15194835 · Cited by 24
“AP-1 is known to be involved in classical senescence, where it drives chromatin accessibility and enhancer activation [89,96,97].”
BackgroundFerreira, F. J., Galhardo, M., Nogueira, J. M., Teixeira, J., Logarinho, E., & Bessa, J. (2025) · Nature Communications · doi:10.1038/s41467-025-57503-4 · Cited by 27
“Onekeyplayer that imprints the senescence cis-regulatory signature is the activator protein 1 (AP-1) complex 14 – 17 .”
InfluentialLiu, X., Zhang, X., Yao, C., Liang, J., Noble, P. W., & Jiang, D. (2024) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2023-0363oc · Cited by 25
“AP-1 has been demonstrated to lead a transcription factor network that drives the transcriptional program of cellular senescence in cell culture (46) and immune aging in murine tissues (47, 48), implying a relevance of the activation of these genes with AT2 cell senescence and in fl ammation in…”
BackgroundAhn, A., Rodger, E. J., Motwani, J., Gimenez, G., Stockwell, P. A., Parry, M. F., Hersey, P., Chatterjee, A., & Eccles, M. R. (2021) · Cancers · doi:10.3390/cancers13174250 · Cited by 21
Aging at the Crossroads of Organ Interactions: Implications for the Heart
Sen, I., Trzaskalski, N. A., Hsiao, Y., Liu, P. P., Shimizu, I., & Dérumeaux, G. (2025) · Circulation Research · doi:10.1161/circresaha.125.325637 · Cited by 20
“232 Because senolytics may have potential safety issues, 123,220 delaying senescence or reprogramming senescent cells could represent a powerful tool to maintain organ structure and function and slow down aging 233 (Figure 3).”
Chen, Z., Mao, Z., Tang, W., Shi, Y., Liu, J., & You, Y. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00517-1 · Cited by 27
“AP-1 drives cellular senescence in glia of CNS in flies [220–222]; however, whether AP-1 also regulates glia cell senescence in mice or humans remains unknown, and deserves further explorations.”
Al‐razaq, M. A. A., Freyter, B. M., Isermann, A., Tewary, G., Mangelinck, A., Mann, C., & Rübe, C. E. (2023) · Cells · doi:10.3390/cells12060916 · Cited by 21
“These findings confirm the previously described hierarchical structure of TF networks with AP-1 as the master regulator to choreograph transcriptional programmes via dynamic interactions with settler and migrant TFs during senescence progression [26].”
BackgroundResultPan, C. C., Maeso‐Díaz, R., Lewis, T. R., Xiang, K., Tan, L., Liang, Y., Wang, L., Yang, F., Yin, T., Wang, C., et al. (2023) · Cell Research · doi:10.1038/s41422-023-00820-4 · Cited by 19
“Of these transcription factors, AP-1 imprints and organizes the senescence enhancer landscape to effectively regulate transcriptional activities that are pertinent to multiple facets of the senescence program.(83) AP-1 is tightly regulated by mitogen-activated protein (MAP) kinases including JNK, p38 and ERK,(84) all…”
BackgroundSenescence: A program in the road to cell elimination and cancer
Moiseeva, O., Guillon, J., & Ferbeyre, G. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.12.017 · Cited by 25
Ji, M.-L., Li, Z., Hu, X. Y., Zhang, W. T., Zhang, H. X., & Lu, J. (2023) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2023.02.011 · Cited by 19
Targeting cellular senescence to combat cancer and ageing
Wang, C., Hao, X., & Zhang, R. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13266 · Cited by 20
Han, Y., Micklem, G., & Kim, S. Y. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101849 · Cited by 16
Sargahydroquinoic acid (SHQA) suppresses cellular senescence through Akt/mTOR signaling pathway
Cao, L., Lee, S. G., Park, S., & Kim, H. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111406 · Cited by 17
Turano, P. S., Akbulut, E., Dewald, H. K., Vasilopoulos, T., Fitzgerald-Bocarsly, P., Herbig, U., & Martínez-Zamudio, R. I. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116795 · Cited by 16
“Intriguingly, and in contrast to our previous results on fibroblasts, 16,17 senescent CD8 + T cells were characterized by inactivation of enhancers to the unmarked, poised, and Polycomb-repressed states (Figures 3A, 3B, and S3B).”
InfluentialSelf-citationThe Role of Endothelial Senescence in the Pathogenesis of Diabetic Retinopathy
Gandhi, M., Haider, S., Chang, H. Z. Y., & Kazlauskas, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115211 · Cited by 17
Guerrero, A., Innes, A. J., Roux, P., Buisman, S. C., Jung, J., Ortet, L., Moiseeva, V., Wagner, V., Robinson, L. J., Ausema, A., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00279-9 · Cited by 15
Self-citationMolecular Characteristics and Promoter Analysis of Porcine COL1A1
Xiang, G., Huang, L., Zhang, X., Wang, N., Wang, H., Mu, Y., Li, K., & Liu, Z. (2022) · Genes · doi:10.3390/genes13111971 · Cited by 17
“In addition, the CEO database showed that the GlI–Krüppel family of zinc finger protein transcription factors (YY1) [32], tryptophan aggregation factor family (ETS1 and SPI1) [33,34], SOX gene family (SOX10) [35,36], and KLF family (KLF1) [37,38] may have no Genes 2022, 13, 1971 11 of 14 significant effect on COL1A1 e…”
BackgroundMethodInfluentialDing, M., Huang, W., Liu, G., Zhai, B., Yan, H., & Zhang, Y. (2023) · BMC Genomics · doi:10.1186/s12864-023-09349-7 · Cited by 16
“FOSL2, JUNB, and ATF3 are members or related genes of the AP-1 superfamily, which has been reported to be a major barrier to human somatic cell reprogramming [40] and to regulate cell aging through the inflammatory response process [41].”
BackgroundSenescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control
Belenki, D., Richter‐Pechańska, P., Shao, Z., Bhattacharya, A., Lau, A., de Freitas, J. A. N. L. F., Kandler, G., Hick, T., Cai, X., Scharnagl, E., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57429-x · Cited by 15
“…primary E μ - myc transgenic mouse B-cell lymphomas with and without genomic ablation of the senescence-essential H3K9 methyltransferase Suv39h1 and further engineered to overexpress Bcl2 as a well-established model for therapy-induced senescence (TIS) 16,25,36 – 39 , 46 ( Supplementary Fig.”
InfluentialSelf-citationSteinhoff, M. S., Alam, M. A., Ahmad, A., Shahab Uddin, M. S., & Buddenkotte, J. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.11.009 · Cited by 17
Chen, Y., Li, Z., Ge, X., Lv, H., & Geng, Z. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1359631 · Cited by 15
Salmiņa, K., Vainshelbaum, N. M., Kreišmane, M., Inashkina, I., Cragg, M. S., Pjanova, D., & Erenpreisa, J. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043237 · Cited by 15
“A GO enrichment analysis of the upregulated bivalent genes of day 5, presented in Figure 3 as a treemap plot, revealed the activation of a stress response and oscillating processes—both typical for r versibl senescence [10,11].”
BackgroundCarroll, C., Manaprasertsak, A., Castro, A. B., van den Bos, H., Spierings, D. C. J., Wardenaar, R., Bukkuri, A., Engström, N., Baratchart, E., Yang, M., et al. (2024) · Cancer Research Communications · doi:10.1158/2767-9764.crc-23-0396 · Cited by 14
“It has been shown to be important in early large-scale genome regulation;andAP-1memberexpressionwasalteredinallcelllinestested(61,62).”
Background
Metadata
- Authors
- Martínez-Zamudio, R. I., Roux, P.-F., de Freitas, J. A. N. L. F., Robinson, L., Doré, G., Sun, B., Belenki, D., Milanovic, M., Herbig, U., Schmitt, C. A., Gil, J., & Bischof, O.
- Affiliations
- Inserm (FR)
- MRC London Institute of Medical Sciences (GB)
- Max Delbrück Center (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Rutgers, The State University of New Jersey (US)
- Johannes Kepler University of Linz (AT)
- Corresponding author
- Bischof, Oliver
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-06-08
- Volume
- 22
- Issue
- 7
- Pages
- 842-855
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC7899185
- OpenAlex
- W3033840227
- Cited by
- 236
- References
- 48
- Citations by year
- 2026: 38 · 2025: 40 · 2024: 39 · 2023: 51 · 2022: 35 · 2021: 26 · 2020: 7
- FWCI
- 18.64
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-09-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Cancer Research UK (28647)
- Agence Nationale de la Recherche (ANR-19-CE13-0017)
- National Cancer Institute (R01CA136533)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, AP-1, transcriptional regulatory networks, epigenetic regulation, Ras-induced senescence, transcriptional programs, transcription factor recruitment, time-resolved transcriptomics, senescence therapy
- MeSH terms
- Animals, Chromatin, Female, Fibroblasts, Gene Expression Regulation, Histones, Humans, Mice, Inbred C57BL, Cellular Senescence, Transcription Factor AP-1, Epigenesis, Genetic, Transcriptome
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