NOTCH1 mediates a switch between two distinct secretomes during senescence
Open accessAbstract
Senescence, a persistent form of cell-cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to 'lateral induction of senescence' through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. As enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared with typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.
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In deeply senescent cells NOTCH1 is lower and the proinflammatory SASP cytokines IL-1, IL-6 and IL-8 are induced.
“At later stages, in deeply senescent cells, NOTCH1 levels are lower, and the SASP proinflammatory cytokines IL-1, IL-6 and IL-8 are induced94.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [94]
In Results, “NOTCH1 signalling is dynamically regulated during senescence” (page unavailable), active NOTCH1 signalling returns near basal levels at full senescence, and IL-6 and IL-8 are primarily upregulated then. But cell-surface NOTCH1 continually increases rather than becoming lower. The paper identifies IL-1 as a proinflammatory SASP component, but the cited passage does not establish that IL-1 is induced specifically at full senescence. (LLM, conf=0.90)
Experimental — accuracy not yet measuredNF-κB and C/EBPβ bind promoters of SASP genes and regulate their activation.
“NF-κB and the transcription factor CCAAT/enhancer-binding protein-β (C/EBPβ) bind promoters of SASP genes and regulate their activation74,93,94”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [94]
In Results (“NOTCH1 regulates senescence secretome through repression of C/EBPβ”; page not provided), the paper reports C/EBPβ binding at the IL1A, IL6 and IL8 promoters and links it to cytokine expression. It also says NF-κB cooperatively regulates the SASP, but does not establish that NF-κB binds SASP-gene promoters. (LLM, conf=0.85)
Experimental — accuracy not yet measuredNotch1 in oncogene-induced senescence and DPP4 in replicative and oncogene-induced senescence are upregulated cell surface markers.
“Recently, two additional upregulated cell surface markers, Notch1 in OIS and DPP4 in replicative and OIS, were identified (Hoare et al., 2016).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Hoare et al., 2016
The Results section, “NOTCH1 is upregulated in OIS” (page unavailable), reports substantial upregulation of cell-surface NOTCH1 during oncogene-induced senescence. Our copy does not report DPP4 as an upregulated marker in replicative or oncogene-induced senescence; searches for DPP4 and CD26 found no supporting passage. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNotch1 and DPP4 have roles in regulating the SASP.
“Both proteins have roles in regulating the SASP.”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Hoare et al., 2016
The Introduction and Results section on NOTCH1’s regulation of TGF-β and pro-inflammatory cytokines show that NOTCH1 regulates SASP composition. Our copy does not establish a SASP-regulating role for DPP4; searches for DPP4 and dipeptidyl peptidase 4 found no supporting passage. Page numbers were not available in the indexed passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn OIS, fluctuations in NOTCH1 levels switch an early TGF-β-rich immunosuppressive secretome to a proinflammatory SASP.
“In OIS, fluctuations in NOTCH1 levels switch an early TGF-β-rich immunosuppressive secretome to a proinflammatory SASP (Hoare et al. 2016).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Hoare et al. 2016
The Results sections on dynamic NOTCH1 signalling and reciprocal secretome regulation (pages unavailable) support an early TGF-β-rich phase followed by a pro-inflammatory phase in oncogene-induced senescence. The immune-clearance Results show that NOTCH1-regulated secretions reduce lymphocyte adhesion, but do not establish that the early TGF-β-rich secretome itself is broadly immunosuppressive. The paper also distinguishes fluctuating NOTCH1 activity from cell-surface NOTCH1 levels, which continued to rise. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Induction of p21 and a Notch-driven SASP are considered early events, whereas upregulation of p16INK4a and an NF-κB-driven SASP are evident at later stages of senescence.
“Induction of p21 and a Notch- driven SASP are considered early events 70,75,76 , whereas upregulation of p16 INK4a and an NF- κB- driven SASP are evident at later stages of senescence 71,77,78 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [70]
The Results section “NOTCH1 signalling is dynamically regulated during senescence” reports transient NOTCH1 activation and a TGF-β-rich secretome during the transition to senescence, supporting the early Notch-driven SASP. It says TGF-β ligands can induce p21, but does not establish that p21 induction itself is an early event. The later p16INK4a and NF-κB clause has separate citations and is not judged here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe SASP is dynamic, changes over time, and varies with the type of senescent cell and how senescence was induced.
“The SASP of senescent cells is not static; it can change over time78–80 and varies depending on the type of cells that became senescent and how senescence was induced16,44,59,60,81.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [78]
Experimental — accuracy not yet measuredEarly in senescence NOTCH1 rises, activates TGF-β and its effectors, and restrains the proinflammatory SASP arm by repressing C/EBPβ.
“NOTCH1 levels increase early on, and NOTCH1 activates transforming growth factor-β and its effectors, while keeping under control the proinflammatory arm of the SASP cascade by repressing its positive regulator C/EBPβ.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [94]
Changes in NOTCH1 activity over the course of senescence alter the makeup of the SASP.
“temporal changes in NOTCH1 activity during senescence have been reported to modulate the composition of SASP.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [94]
NOTCH1 signaling is critical to paracrine secretion in senescent cells.
“which is critical to paracrine secretion in senescent cells (Hoare et al., 2016).”
From Single senescent cell sequencing reveals heterogeneity in senescent cells induced by telomere erosion (2019) · cites this paper as Hoare et al., 2016
Senescent cells can communicate via direct cell-cell contact, cell fusion, cytoplasmic bridges, extracellular vesicle signaling, and the SASP.
“Senescent cells can communicate via direct cell-cell contact (Nelson et al. 2012; Hoare et al. 2016), cell fusion (Chuprin et al. 2013), through the formation of cytoplasmic bridges (Biran et al. 2017), by extracellular vesicle (EV) signaling (Takasugi et al. 2017), and through the SASP.”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Hoare et al. 2016
The SASP is not stable, instead being highly dynamic.
“Like many other senescence- associated features, however, the SASP is not stable, instead being highly dynamic 6,70,71 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [70]
NOTCH1 inhibition facilitates upregulation of proinflammatory SASP components.
“In accordance with this, NOTCH1 inhibition has been shown to facilitate the upregulation of proinflammatory SASP components (Hoare et al., 2016; Ito et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Hoare et al., 2016
NOTCH1 mediated suppression of inflammatory cytokines is manifested primarily by repression of c/EBPβ mediated transcription and not NF-κB.
“This NOTCH1 mediated suppression of inflammatory cytokines is manifested primarily by the repression of c/EBPβ mediated transcription and not NF-κB.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Hoare et al., 2016
NOTCH1 dynamic signaling is crucial regulator of SASP composition governing transition between inflammatory secretome and TGF-β enriched secretome.
“Recent findings have indicated dynamic signaling by NOTCH1, a transmembrane receptor, as a crucial regulator of SASP composition which governs the transition between the inflammatory secretome and TGF-β enriched secretome.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Hoare et al., 2016
In OIS, NOTCH1 activity correlates with expression of TGF-β1 and TGF-β3 factors and inversely correlates with expression of typical inflammatory cytokines such as IL1A, IL-6, and IL-8.
“In OIS, NOTCH1 activity correlates with the expression of TGF-β1 and TGF-β3 factors and inversely corelates with expression of typical inflammatory cytokines such as IL1A, IL-6, and IL-8.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Hoare et al., 2016
Senescent cells can communicate with surroundings through juxtacrine NOTCH/JAG1 signaling or ROS secretion or cargo transfer by cytoplasmic bridges or release of extracellular vesicles such as exosomes.
“Senescent cells can communicate with the surroundings through juxtacrine NOTCH/JAG1 signaling (Hoare et al., 2016; Ito et al., 2017) or ROS secretion (Kuilman et al., 2010; Nelson et al., 2012, 2018) or cargo transfer by formation of cytoplasmic bridges (Biran et al., 2015) or release of extracellular vesicles such exosomes (Lehmann et al., 2008; Takasugi et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Hoare et al., 2016
The senescence-associated secretory phenotype consists of pro-inflammatory cytokines, proteases, chemokines, and extracellular matrix degrading proteins.
“The SASP consists of a noxious secretome comprised of pro-inflammatory cytokines, proteases, chemokines, and extracellular matrix degrading proteins (24–27).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [26]
NOTCH1 shows temporal changes during OIS.
“This pattern highly resembles the recently described temporal changes induced by NOTCH1 during OIS”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Hoare et al., 2016
TGF-β ligands are part of the SASP and play an important role in senescence through p21CIP regulation.
“a number of studies have found that TGF-β ligands are part of the SASP and play an important role in senescence through p21CIP regulation, in agreement with our data (Acosta et al., 2013, Hoare et al., 2016, Muñoz-Espín et al., 2013, Storer et al., 2013).”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Hoare et al., 2016
Time-series transcriptomic profiling studies indicate that SASP composition changes in a temporal manner during the establishment of cellular senescence.
“Time-series transcriptomic profiling studies indicate that the SASP composition changes in a temporal manner during the establishment of cellular senescence [150].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [150]
NOTCH activity in OIS enables a switch from an early pro-regenerative secretome associated with TGF-β to a late secretome rich in inflammatory factors.
“Particularly, NOTCH activity in OIS enables a switch from an early pro-regenerative secretome associated with TGF-β to a late secretome rich in inflammatory factors (i.e., inflammatory SASP) [150].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [150]
At later stages of senescence, NOTCH1 expression decreases, entailing activation of C/EBPβ and subsequent production of the inflammatory SASP.
“This inhibition is transient, and at later stages of senescence, NOTCH1 expression decreases, entailing the activation of C/EBPβ and the subsequent production of the inflammatory SASP [150].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [150]
The composition and intensity of the SASP response can be affected by the senescence-inducing mechanism, cell type, and time since senescence initiation, indicating that there is no singular SASP.
“The composition and intensity of the SASP response can be affected by several factors including the senescence-inducing mechanism, cell type, and the amount of time passed since senescence initiation, indicating that there is no singular SASP.12–17”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [16]
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Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies
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Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer
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Notch Signaling Mediates Secondary Senescence
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- Authors
- Hoare, M., Ito, Y., Kang, T.-W., Weekes, M. P., Matheson, N. J., Patten, D. A., Shetty, S., Parry, A. J., Menon, S., Salama, R., Antrobus, R., Tomimatsu, K., Howat, W., Lehner, P. J., Zender, L., & Narita, M.
- Affiliations
- University of Cambridge (GB)
- German Cancer Research Center (DE)
- University of Birmingham (GB)
- Corresponding author
- Narita, Masashi
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2016-08-15
- Volume
- 18
- Issue
- 9
- Pages
- 979-992
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC5008465
- OpenAlex
- W2518194013
- Cited by
- 522
- References
- 68
- Citations by year
- 2026: 55 · 2025: 45 · 2024: 60 · 2023: 63 · 2022: 71 · 2021: 62 · 2020: 56 · 2019: 47 · 2018: 42 · 2017: 17 · 2016: 4
- FWCI
- 29.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (108070/Z/15/Z, 101835/Z/13/Z, WT101835, 093964/Z/10/Z, 101835, 093964, 097162, 108070, 097162/Z/11/Z)
- Cancer Research UK (C14303_do not transfer, A10183, 19159, A19924, A19159, CB4210, 19924, C14303 / A17197, 15890, CRUK-A19924, 22310)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- Notch1 signaling, senescence-associated secretome, oncogene-induced senescence, TGF-beta, inflammatory cytokines, C/EBPβ, JAG1, lymphocyte recruitment, cell cycle arrest
- MeSH terms
- Animals, Humans, Mice, Transgenic, Transforming Growth Factor beta, Cellular Senescence, Cell Line, Tumor, Receptor, Notch1, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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