mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Open accessAbstract
Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
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Rapamycin and its analogue RAD001 reduced the protumorigenic SASP, prevented senescence, impaired SASP-mediated immune recognition of oncogene-expressing cells, and improved liver dysfunction in naturally aged mice.
“Treatment with rapamycin (and its analogue RAD001)232 attenuated the protumorigenic SASP230, prevented senescence233, impaired SASP-mediated immune recognition of oncogene-expressing cells and ameliorated liver dysfunction in naturally aged mice231.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [230]
The Results section ('mTOR inhibition also blunts the tumour suppressive effects of the SASP'; page unavailable) reports that rapamycin impaired SASP induction and reduced immune-cell infiltration in mice with oncogene-expressing hepatocytes, supporting the immune-surveillance part of the claim. The Results section ('mTOR inhibition prevents the induction of the SASP'; page unavailable) reports lower liver SASP levels in aged rapamycin-treated mice, but does not report improved liver dysfunction. The RAD001, protumorigenic-SASP and senescence clauses have separate citations in the citing sentence and are not judged here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe mTOR pathway, which coordinates cell growth and metabolism according to nutrient availability, also drives SASP production by increasing translation of certain mRNAs, including the membrane-bound NF-κB regulator IL-1α.
“These include, for example, the mammalian target of rapamycin (mTOR) pathway, which coordinates cell growth and metabolism in response to nutrients, and also promotes SASP production through increased translation of subsets of mRNAs, including the membrane-bound and upstream regulator of NF-κB, IL-1α230”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [230]
The Introduction (page not specified) says mTOR responds to nutrient signals, and the Results report that mTOR inhibition reduces SASP induction and IL-1α mRNA’s association with polysomes. However, the Discussion identifies increased MAPKAPK2 translation—not IL-1α translation—as the mechanism controlling the SASP. The passages do not describe IL-1α as membrane-bound or an upstream NF-κB regulator. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe nutrient sensing pathways mTOR and NAD are involved in SASP regulation.
“In addition, the nutrient sensing pathways, mTOR and NAD, are involved in SASP regulation.56, 57, 58”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [57]
The Results section (‘mTOR inhibition prevents the induction of the SASP’; page not provided) reports that mTOR depletion and inhibition reduced SASP factors, supporting the mTOR part of the sentence. The cited paper does not address NAD’s involvement in SASP regulation, so it does not support the full claim. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlkylating agents, topoisomerase inhibitors, γ-irradiation, microtubule inhibitors and, to a lesser extent, vinca alkaloids have all been identified as senescence inducers in preclinical models.
“Alkylating agents 27,95,96 (for example, cisplatin, cyclophosphamide and temozolomide), topoisomerase inhibitors 27,65,91,95 (such as doxorubicin, etoposide and camptothecin) and γ- irradiation 78 , but also microtubule inhibitors 27,97,98 (for example, paclitaxel) and, to a lesser extent, vinca alkaloids 78 (for example, vincristine), have all been identified as senescence inducers in preclinical”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [65]
The Results section describes fibroblasts that underwent irradiation-induced senescence, supporting the γ-irradiation part of the citation. The paper does not identify vinca alkaloids or vincristine as senescence inducers; those are the other agents for which this citation is attached. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe mTOR inhibitor rapamycin has the context-dependent potential to induce senescence, diminish NF-κB activity, suppress the pro-inflammatory SASP at the translational level, and limit the growth-promoting effect of senescent bystander fibroblasts on prostate tumours.
“In various preclinical studies, the mTOR inhibitor rapamycin might have the context-dependent potential to induce senescence 45 , diminish NF-κB activity 65,66 , suppress the pro-inflammatory SASP at the translational level, and limit the growth-promoting effect of senescent bystander fibroblasts on prostate tumours 66 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [65]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
NF-κB, p38, mTOR and C/EBPβ signalling pathways are major components of the SASP.
“The NF- κB, p38, mTOR and C/EBPβ signalling pathways are major components of the SASP 63-67 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [65]
mTOR differentially regulates translation of IL-1A and MAPKAP2 through 4EBP1.
“It also differentially regulates translation of IL-1A, the master regulator of SASP that subsequently engages IL-6/IL-8 (Orjalo et al., 2009; Laberge et al., 2015) and MAP kinase-activated protein kinase 2 (MAPKAP2) through 4EBP1, a translation repressor protein (Herranz et al., 2015).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Herranz et al., 2015
Inhibition of mTOR by rapamycin suppresses secretion of inflammatory cytokines by senescent cells.
“Inhibition of mTOR by rapamycin suppresses the secretion of inflammatory cytokines by senescent cells (Herranz et al., 2015; Laberge et al., 2015).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Herranz et al., 2015
Hypoxia impairs mTOR activity, leading to reduced IL-1α translation to support NF-κB activity and SASP induction.
“Hypoxia impairs mammalian target of rapamycin (mTOR) activity, leading to reduced IL-1α translation to support NF-κB activity and SASP induction [162,163].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [162]
MAPKAPK2 phosphorylates ZFP36L1, preventing its binding to and ability to degrade SASP RNAs.
“MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1, thus preventing its binding to and its ability to degrade SASP RNAs [162].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [162]
An increase in mTORC1 activity is essential for implementing the SASP by modulating translation of IL-1α and MAPKAPK2.
“The increase in mTORC1 activity is essential for implementing the SASP by modulating the translation of IL-1α and MAP kinase-activated protein kinase 2 (MAPKAPK2) [162,163].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [162]
Inhibition of MK2 by rapamycin results in a decrease in cytokine expression.
“inhibition of MK2 by rapamycin results in a concomitant decrease in cytokine expression”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Herranz et al., 2015
mTOR activates translation of MAPKAPK2 (MK2).
“Herranz et al. showed that mTOR activates the translation of MAPKAPK2 (MK2), a Ser/Thr‐kinase downstream of the MAP kinase p38”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Herranz et al., 2015
MK2 stabilizes mRNAs and upregulates expression of many cytokines.
“It has been observed that MK2 stabilizes the mRNAs and upregulate the expression of many cytokines”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Herranz et al., 2015
Inhibition of mTOR by rapamycin selectively inhibits SASP and SA β-gal staining of senescent cells without affecting cell cycle arrest.
“inhibition of mTOR by rapamycin selectively inhibits the SASP and SA β‐gal staining of senescent cells without affecting their cell cycle arrest”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Herranz et al., 2015
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- Authors
- Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., Georgilis, A., Montoya, A., Wolter, K., Dharmalingam, G., Faull, P., Carroll, T., Martínez-Barbera, J. P., Cutillas, P., Reisinger, F., Heikenwalder, M., Miller, R. A., Withers, D., Zender, L., Thomas, G. J., & Gil, J.
- Affiliations
- Imperial College London (GB)
- Cancer Research UK (GB)
- University of Tübingen (DE)
- Helmholtz Munich (DE)
- University of Michigan (US)
- Corresponding author
- Gil, Jesús
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2015-08-17
- Volume
- 17
- Issue
- 9
- Pages
- 1205-1217
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4589897
- OpenAlex
- W1910950086
- Semantic Scholar
- e5c6b05dd1b15397beb7118765439b028758f8ce
- Cited by
- 788
- References
- 61
- Citations by year
- 2026: 88 · 2025: 68 · 2024: 81 · 2023: 86 · 2022: 97 · 2021: 81 · 2020: 76 · 2019: 64 · 2018: 54 · 2017: 48 · 2016: 39 · 2015: 6
- FWCI
- 36.07
- Type
- journal article
- Language
- en
- Update notices
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Wellcome Trust (098565, 098565/Z/12/Z)
- Cancer Research UK (16243, 13315)
- National Institutes of Health
- Medical Research Council (MR/M000125/1)
- Biotechnology and Biological Sciences Research Council (BB/H020527/2)
- National Institute on Aging (P01AG031736, P30AG024824, U01AG022303)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- mTOR, senescence-associated secretory phenotype, MAPKAPK2, 4E-BP1, ZFP36L1, translational regulation, mRNA degradation, rapamycin, cellular senescence, tumor suppression, tumor promotion, age-related diseases, immune surveillance
- MeSH terms
- MAP-Kinase-Activated Kinase 2, Animals, Female, Humans, Mice, Nude, Neoplasm Transplantation, Phosphoproteins, Protein Biosynthesis, Cellular Senescence, Protein Serine-Threonine Kinases, Proteome, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, HEK293 Cells, TOR Serine-Threonine Kinases
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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