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Cited by 193Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsTGF-β signaling in diseases

Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway

Open access
Rapisarda, Valentina, Borghesan, Michela, Miguela, Veronica, Encheva, Vesela, Snijders, Ambrosius P., Lujambio, Amaia, O’Loghlen, Ana·2017·Cell Reports
DOI 10.1016/j.celrep.2017.02.012PMC PMC5357738
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Abstract

Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanisms regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3) is regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β) pathway in a cell-autonomous and non-cell-autonomous manner. β3 levels are dynamically increased during oncogene-induced senescence (OIS) through CBX7 Polycomb regulation, and downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS), independently of its ligand-binding activity. Moreover, cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP) without affecting proliferation. Finally, we show an increase in β3 levels in a subset of tissues during aging. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.

AI snapshot

Written from the paper’s full text.

TL;DR

ITGB3/β3 is a CBX7/PRC1-regulated gene whose expression rises during oncogene-, therapy-, DNA-damage-, and replicative senescence and aging, and β3 promotes senescence via p53/p21 and TGF-β signaling largely independently of ligand binding. Cilengitide blocks the SASP without reversing growth arrest, suggesting αvβ3 as a way to uncouple inflammation from senescence.

Key findings

  • SILAC in CBX7-knockdown human primary breast fibroblasts identified 82 proteins with a 2-fold expression difference in both forward and reverse experiments, including CDKN2A; ECM-receptor interaction and focal adhesion pathways were upregulated. Of these, 20 proteins had genes potentially bound by CBX proteins, and CBX7 knockdown upregulated the majority of the 20 genes more than 2-fold by qPCR, with CBX7 ChIP enrichment at the ITGB3 TSS.
  • ITGB3 ectopic expression in BFs reduced BrdU incorporation, increased p21CIP/p53, CDKN2B mRNA, SA-β-Gal activity, ROS, and mild SASP mRNAs, without a DNA-damage response; shp53 or sip53 impaired the growth arrest and SA-β-Gal increase. ITGB3 mRNA was dynamically upregulated during OIS (RAS), DDIS (etoposide), and TIS (Palbociclib), with ITGB3 the most upregulated among ITGB1–8 during OIS, and CBX7 binding at the ITGB3 TSS was reduced during OIS.
  • sh/siITGB3 impaired RAS- and Palbociclib-induced proliferation arrest and partially reverted p21CIP; cilengitide did not reverse proliferation arrest or p21CIP/p16INK4A upregulation but significantly reduced secreted IL-8 and IL-6. TGFBR1, cilengitide, ROCK1/2, and ILK inhibitors reversed β3-induced proliferation arrest and p21CIP; siTGFBR2 overcame ITGB3-induced senescence; ITGB3 increased TGF-β pathway regulators, nuclear SMAD2/3, and MMP1/MMP9, and conditioned media from ITGB3 cells induced p53 stabilization, SMAD2/3 nuclear translocation, and reduced proliferation in normal BFs, blocked by anti-TGF-β1–3 or TGFBR1 inhibitor.
  • In C57BL/6J female mice aged 4, 19, and 25 months, liver showed dynamic increases in Cdkn2a and Itgb3, highest at 25 months, with upregulation also in kidney and intestine. Human skin fibroblasts from old (~80 years) versus young (~10 years) donors showed reduced proliferation, increased p16INK4A/p21CIP, increased β3 protein/RNA and αvβ3 focal-adhesion staining, and increased TGF-β receptors 1/2 and SMAD3/4; siITGB3 or sip53 overcame the proliferation arrest and partially reverted p21CIP, while cilengitide did not attenuate senescence.

Methods

  • SILAC quantitative proteomics compared human primary breast fibroblasts transduced with shCBX7 versus empty vector in forward and reverse labeling experiments, integrated with published CBX ChIP-seq, qPCR, and endogenous CBX7 ChIP.
  • Cell-based assays used human primary fibroblasts (BFs, IMR-90), MCF7, SK-HEP-1, mouse fibroblasts, and mouse hepatic stellate cells with retroviral/lentiviral expression (ITGB3, ITGB3D119A, RAS, TRF2ΔBΔM), RNAi (sh/siITGB3, shp53/sip53, siTGFBR2), small-molecule inhibitors (cilengitide, TGFBR1, ROCK1/2, ILK, Palbociclib), BrdU, IF, immunoblot, qPCR, SA-β-Gal, ROS, and conditioned-media assays.
  • Aging analyses used RNA from liver, kidney, and intestine of C57BL/6J female mice aged 4, 19, and 25 months and primary skin fibroblasts from young (~10 years) and old (~80 years) human donors; statistics used mean ± SD, Student’s t test, and p < 0.05 as significant.

Limitations

  • Stated: TGF-β could not be detected in the supernatant; pan-specific neutralizing anti-TGF-β1–3 antibodies did not reproduce the cell-autonomous effect seen with TGFBR2 knockdown; and cilengitide unexpectedly affected proliferation in the ITGB3-overexpression setting, possibly due to αvβ5 compensation.
  • Evident from the text: several key results are reported as “data not shown” (e.g., TGF-β in supernatant, neutralizing-antibody cell-autonomous result, CXCR2 mRNA, ITGB5 upon ITGB3 expression), limiting assessment; no in vivo genetic manipulation of ITGB3 in mice is reported, so the aging evidence is correlative plus knockdown in human donor fibroblasts.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2017.02.012

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    β3 levels are dynamically increased during oncogene-induced senescence through CBX7 Polycomb regulation.

    “β3 levels are dynamically increased during oncogene-induced senescence (OIS) through CBX7 Polycomb regulation”
    Quote in the paperSubstantial claim
  • Findingown data

    SILAC analysis of CBX7 knockdown in human primary fibroblasts identified 82 proteins with a 2-fold expression difference in both forward and reverse experiments, including CDKN2A.

    “Combination of the results from both forward and reverse experiments show 82 proteins with a 2-fold expression difference in both experiments, including CDKN2A”
    Quote in the paperSubstantial claim
  • Findingown data

    β3 levels increase in a subset of tissues during aging.

    “we show an increase in β3 levels in a subset of tissues during aging.”
    Quote in the paperNot a substantial claim
  • Findingown data

    ITGB3 is regulated by the Polycomb protein CBX7 in human primary fibroblasts.

    “Here, we find that ITGB3 (integrin beta 3 or β3) is regulated by the Polycomb protein CBX7.”
    • Also stated in: § ITGB3 Is Regulated by PRC1 · plain
      “Altogether, these data show that the ITGB3 locus is regulated by the Polycomb protein CBX7 in human primary fibroblasts.”
    Quote in the paperSubstantial claim
  • Findingown data

    qPCR analyses show upregulation of a range of regulators implicated in the TGF-β pathway in BFs expressing ITGB3.

    “qPCR analyses of a range of regulators implicated in the TGF-β pathway are upregulated in BFs expressing ITGB3”
    Quote in the paperSubstantial claim
  • May combine two claims. 37
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    Downregulation of β3 levels overrides oncogene-induced senescence and therapy-induced senescence.

    “downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS), independently of its ligand-binding activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cilengitide, an αvβ3 antagonist, blocks the senescence-associated secretory phenotype without affecting proliferation.

    “cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP) without affecting proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Livers from mice aged 19 months show dynamic increase in mRNA levels of Cdkn2a and Itgb3, with highest increase in 25-month-old mice where additional markers of senescence were observed.

    “Livers from mice aged 19 months presented a dynamic increase at the mRNA levels of Cdkn2a and Itgb3, but the highest increase was observed in 25-month-old mice, where additional markers of senescence were observed”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During OIS in BFs stably expressing RAS, integrin beta subunits are deregulated, with upregulation of ITGB1, 3, 4, and 6, and ITGB3 is the most upregulated.

    “Our data show a noticeable deregulation of integrin beta subunits during OIS, with upregulation of ITGB1, 3, 4, and 6 during RAS expression, ITGB3 being the subunit most upregulated”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Conditioned media from ITGB3-expressing cells induces stabilization of p53, nuclear translocation of SMAD2/3, and reduced proliferation in normal BFs.

    “we did find that the conditioned media (CM) from cells expressing ITGB3 had an effect on normal BFs by inducing the stabilization of p53 protein (Figure 5H), the nuclear translocation of SMAD2/3 (Figure 5I), and a reduced proliferation rate (Figure S5C) in normal BFs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pan-specific neutralizing anti-TGF-β1-3 antibodies do not reproduce the effect of TGFBR2 knockdown, suggesting ITGB3 regulates TGF-β at least partially in a cell-autonomous fashion.

    “we could not reproduce these results using pan-specific neutralizing anti-TGF-β1–3 antibodies (data not shown), suggesting that ITGB3 regulates TGF-β, at least partially, in a cell-autonomous fashion.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Cilengitide treatment during OIS significantly reduces SASP, as measured by IL-8 and IL-6 secreted to supernatant.

    “we did observe a significant reduction of the SASP, as shown by measuring the levels of IL-8 and IL-6 secreted to the supernatant by immunoblot”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpression of murine Cbx7 resulted in gene silencing and transcriptional repression.

    “while overexpression of murine Cbx7 resulted in gene silencing and transcriptional repression”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cilengitide treatment of BFs expressing RAS cannot reverse proliferation arrest or upregulation of p21CIP or p16INK4A protein levels.

    “treatment of BFs expressing RAS with cilengitide could not reverse the proliferation arrest (Figure 4H) or the upregulation of p21CIP or p16INK4A protein levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mHSCs from adult mouse with Dox-inducible shp53, upon Dox withdrawal senescence is induced by re-expression of p53 and mHSCs show increase in markers of senescence concomitant with accumulation of Itgb3.

    “Upon Dox withdrawal, senescence is induced by re-expression of p53 and mHSCs showed an increase in a number of markers of senescence (Figure S6A), concomitant with the accumulation of Itgb3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lujambio et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Upregulation of Itgb3 mRNA and other markers of senescence are also observed in kidney and, to a lesser extent, intestine in 25-month-old mice.

    “Upregulation of Itgb3 mRNA and other markers of senescence were also observed in kidney (Figures 6D and S6B) and, to a lesser extent, in the intestine in 25-month-old mice”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ChIP for endogenous CBX7 in BFs showed enrichment at the TSS of analyzed genes, including INK4A, but not negative controls ARF or ACTB.

    “Our data show enrichment for CBX7 at the TSS of the analyzed genes, including INK4A (encoding p16INK4A), but not the negative controls ARF (encoding p14ARF) or ACTB (encoding β-actin)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transduction of BFs expressing RAS with shITGB3 or transfection with siITGB3 impairs proliferation arrest induced by RAS and partially reverts increase in p21CIP.

    “The transduction of BFs expressing RAS with an shRNA targeting ITGB3 (shITGB3) or transfection with two different siRNAs (siITGB3) impaired the proliferation arrest induced by RAS (Figures 4F, S3F, left panel, and S3G) and partially reverted the increase in the cell-cycle inhibitor p21CIP induced upon OIS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    shRNA targeting TP53 impairs proliferation arrest and increase in SA-β-Gal activity induced by ITGB3.

    “we impaired not only the proliferation arrest induced by ITGB3 (Figure 3G, left panel) but also the increase in SA-β-Gal activity”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Acosta et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    ITGB3 expression also induces senescence in IMR-90 fibroblasts, indicating the response is not strain specific.

    “ITGB3 expression also induced senescence in IMR-90 fibroblasts, indicating that this response is not strain specific”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ITGB3 expression increases protein levels of p21CIP and p53 and CDKN2B mRNA levels, with no changes in CDKN2A or CDKN1B.

    “we observed an increase in the protein levels of the cell-cycle inhibitors p21CIP and p53 by IF (Figure 3B) and CDKN2B mRNA levels by qPCR, with no changes observed in CDKN2A or CDKN1B”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with pan-specific neutralizing anti-TGF-β1-3 antibody or TGFBR1 inhibitor abrogates the effect of conditioned media from ITGB3 cells.

    “treatment with a pan-specific neutralizing anti-TGF-β1-3 antibody (Figure 5H) or an inhibitor for TGFBR1 (Figure 5I) abrogated the effect of the CM from ITGB3 cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In IMR-90 ER:RAS cells, ITGB3 mRNA is downregulated at early timepoints but consistently upregulated during establishment of senescence.

    “Though the mRNA levels of ITGB3 at early timepoints of the induction of senescence were downregulated, we did observe a consistent upregulation of ITGB3 during the establishment of senescence”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In SK-HEP-1 cells, ITGB3 mRNA upregulation is observed only after 10 days of Palbo treatment, concomitant with establishment of senescence.

    “the upregulation of ITGB3 mRNA levels in SK-HEP-1 cells could only be observed after 10 days of treatment with Palbo, concomitant with the establishment of senescence”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PRC1 complex regulates the ITGB3 locus in normal fibroblasts, and CBX7 binding to the ITGB3 TSS is reduced during OIS.

    “Our results further add PRC1 complex as a regulator of the ITGB3 locus in normal fibroblasts and for CBX7 during OIS, where CBX7 binding to the ITGB3 TSS is reduced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cilengitide has a diverse effect on the SASP and on the senescence growth arrest.

    “Our data show that cilengitide has a diverse effect on the SASP and on the senescence growth arrest.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of old donor cells with cilengitide does not attenuate senescence, neither proliferation arrest nor p21CIP upregulation.

    “Treatment of old donor cells with cilengitide could not attenuate senescence, neither the proliferation arrest nor p21CIP upregulation (Figures 7E and 7F)”
    • Also stated in: § Discussion · hedged
      “However, the αvβ3 antagonist, cilengitide, could not reverse aging, suggesting that the role for β3 in this cellular system is independent of its ligand-binding activity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Integrin αvβ3 can induce apoptosis, tumor progression, and tumor stemness in an anchorage-independent manner.

    “In fact, integrin αvβ3 can induce apoptosis (Stupack et al., 2001), tumor progression (Desgrosellier et al., 2009), and tumor stemness (Seguin et al., 2014) in an anchorage-independent manner.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Stupack et al., 2001 source

      Not checked in the free run.

    • cites Desgrosellier et al., 2009 source

      Not checked in the free run.

    • cites Seguin et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Senescent cells secrete inflammatory proteins, growth factors, and metalloproteases that constitute the SASP.

    “In fact, senescent cells secrete an array of inflammatory proteins, growth factors, and metalloproteases that collectively constitute the SASP (senescence-associated secretory phenotype).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pérez-Mancera et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    p16INK4A-positive cells accumulate during aging and contribute to age-related dysfunctions in different tissues.

    “a recent study has demonstrated that p16INK4A-positive cells accumulate during aging and contribute to age-related dysfunctions in different tissues.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baker et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The senescence program can be triggered by oncogene activation, drug treatment, or deregulation of PRC1 proteins including CBX7.

    “The senescence program can be triggered by a number of stressors, like the activation of oncogenes (termed oncogene-induced senescence; OIS), drug treatment (therapy-induced senescence; TIS) or deregulation of Polycomb Repressive Complex 1 (PRC1) proteins, including the polycomb protein chromobox 7 (CBX7)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gil and O’Loghlen, 2014

      Not checked in the free run.

    • cites Salama et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Integrins can mediate signaling cascades independent of ligand binding.

    “Interestingly, integrins can also mediate signaling cascades independent of ligand binding.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Stupack et al., 2001 source

      Not checked in the free run.

    • cites Desgrosellier et al., 2009 source

      Not checked in the free run.

    • cites Seguin et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Integrin β3 subunit is a marker and regulator of senescence.

    “Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.”
    • Also stated in: § Introduction · boosted
      “Here, we establish integrin beta 3 (β3) subunit as a marker and regulator of senescence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elimination of senescent cells reverses the aging phenotype and stimulates tissue regeneration, demonstrating that activation of senescence is a direct cause of aging.

    “Thus, the elimination of senescent cells reverses the aging phenotype and stimulates tissue regeneration, demonstrating that the activation of senescence is a direct cause of aging”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baker et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the TGF-β pathway in a cell-autonomous and non-cell-autonomous manner.

    “β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β) pathway in a cell-autonomous and non-cell-autonomous manner.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The shRNA targeting TP53 (shp53) used was previously characterized.

    “Using a previously characterized shRNA targeting TP53 (shp53)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Acosta et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    ITGB3 ectopic expression induces senescence in human primary fibroblasts, dependent on the p53/p21CIP pathway.

    “Thus, ITGB3 ectopic expression induces senescence in human primary fibroblasts, which is dependent on the p53/p21CIP pathway.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NOTCH1 shows temporal changes during OIS.

    “This pattern highly resembles the recently described temporal changes induced by NOTCH1 during OIS”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoare et al., 2016 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Upon binding of TGF-β ligands with TGFBRs, the pathway becomes active and specific SMAD proteins translocate to the nucleus to control gene expression.

    “Upon binding of TGF-β ligands with TGFBRs, the pathway becomes active, and specific SMAD proteins translocate to the nucleus to control gene expression”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schmierer and Hill, 2007

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activation of cellular senescence is considered one of the hallmarks of aging.

    “the activation of cellular senescence is considered one of the hallmarks of aging”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites López-Otín et al., 2013 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Integrins activate TGF-β.

    “integrins are known to activate TGF-β”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Asano et al., 2005 source

      Not checked in the free run.

    • cites Margadant and Sonnenberg, 2010 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    TGF-β regulates senescence.

    “previous reports have shown that TGF-β regulates senescence”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Acosta et al., 2013 source

      Not checked in the free run.

    • cites Muñoz-Espín et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    ITGB3 expression also induced senescence in IMR-90 fibroblasts, indicating that this response is not strain specific.

    “ITGB3 expression also induced senescence in IMR-90 fibroblasts, indicating that this response is not strain specific”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Expression of TRF2ΔBΔM in primary fibroblasts rapidly mimics replicative senescence and aging.

    “Expression of TRF2ΔBΔM in primary fibroblasts rapidly mimics the process of replicative senescence and aging”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Karlseder et al., 1999 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Developmental senescence is activated to promote tissue remodeling and stem cell renewal.

    “Interestingly, developmental senescence is activated to promote tissue remodeling and stem cell renewal (Muñoz-Espín and Serrano, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Muñoz-Espín and Serrano, 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Acosta et al., 2013 source

      Not checked in the free run.

    • cites Hoare et al., 2016 source

      Not checked in the free run.

    • cites Muñoz-Espín et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MYC overexpression leads to direct downregulation of ITGB3, inducing decreased motility and invasiveness.

    “A recent report has found that MYC overexpression leads to a direct downregulation of ITGB3, inducing decreased motility and invasiveness (Liu et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Senescent cells accumulate during aging, causing chronic inflammation.

    “As senescent cells accumulate during aging, causing chronic inflammation (van Deursen, 2014)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites van Deursen, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    β3-induced senescence presents a similar pattern to developmental senescence (activation of p21CIP, TGF-β/SMAD, and no DNA damage) and is independent of ligand binding.

    “Our data show that senescence induced by β3 presents a similar pattern to developmental senescence (activation of p21CIP, TGF-β/SMAD, and no DNA damage) and that it is independent of ligand binding.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cilengitide effectively inhibits αvβ3 ligand-binding activity in old donor fibroblasts.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ITGB3 has been previously identified as a Polycomb target by ChIP sequencing in mouse embryonic stem cells and human primary fibroblasts.

    “ITGB3 has been previously identified as a Polycomb target by ChIP sequencing in other biological contexts, such as mouse embryonic stem cells (ESCs) (Morey et al., 2013) and human primary fibroblasts (Pemberton et al., 2014)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Morey et al., 2013 source

      Not checked in the free run.

    • cites Pemberton et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cross-talk between integrins and TGF-β exists, particularly to regulate fibrosis, wound healing, and cancer.

    “Accumulating evidence indicates that a cross-talk between integrins and TGF-β exists, in particular to regulate fibrosis, wound healing, and cancer (Asano et al., 2005, Margadant and Sonnenberg, 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Asano et al., 2005 source

      Not checked in the free run.

    • cites Margadant and Sonnenberg, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    β3 subunit expression accelerates the onset of senescence in human primary fibroblasts, dependent on activation of the p21CIP/p53 pathways.

    “We show that β3 subunit expression accelerates the onset of senescence in human primary fibroblasts, which is dependent on the activation of the p21CIP/p53 pathways.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The care and use of mice were in accordance with the UK Home Office regulations and the UK Animals (Scientific Procedures) Act of 1986.

    “The care and use of mice were in accordance with the UK Home Office regulations and the UK Animals (Scientific Procedures) Act of 1986.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    p16INK4A levels correlate with chronological age in most tissues analyzed, both in mice and in humans.

    “This is in accordance with previous reports, which have found that p16INK4A levels correlate with chronological age in most tissues analyzed, both in mice (Baker et al., 2016, Krishnamurthy et al., 2004) and in humans (Ressler et al., 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Baker et al., 2016 source

      Not checked in the free run.

    • cites Krishnamurthy et al., 2004 source

      Not checked in the free run.

    • cites Ressler et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The β3 subunit is a marker and regulator of senescence.

    “In summary, here, we provide evidence for the β3 subunit being a marker and regulator of senescence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Integrins can direct specific stemness-related reprogramming, providing an important role during development independent of their ligand-binding activity.

    “Furthermore, integrins can direct specific stemness-related reprogramming, providing an important role during development independent of their ligand-binding activity (Seguin et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Seguin et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    αvβ3 expression is increased in a number of cell types undergoing tissue remodeling.

    “In fact, αvβ3 expression is increased in a number of cell types undergoing tissue remodeling (Asselin-Labat et al., 2007, Brooks et al., 1994).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Asselin-Labat et al., 2007 source

      Not checked in the free run.

    • cites Brooks et al., 1994 source

      Not checked in the free run.

52 of 52

  • The paper relies on this without support.

    Integrins can activate TGF-β embedded in the ECM by increasing expression of matrix-degrading enzymes (MMPs) and proteolytic release of TGF-β to the media.

    “Integrins can activate TGF-β embedded in the ECM by increasing the expression of matrix-degrading enzymes (matrix metalloproteinases; MMPs) and the proteolytic release of TGF-β to the media.”

  • The paper relies on this without support.

    Cilengitide effectively inhibits αvβ3 ligand-binding activity in old donor fibroblasts.

    “suggesting that the role for ITGB3 in aging in human primary fibroblasts is independent of its ligand-binding activity.”

  • The paper relies on this without support.

    Increased mRNA levels of TGF-β receptors 1 and 2 and SMAD3 and 4 reflect activation of the TGF-β pathway.

    “we could also observe an increase in the mRNA levels of different regulators of the TGF-β pathway, including TGF-β receptors 1 and 2 and SMAD3 and 4 (Figure 6G).”

  • The paper relies on this without support.

    The primary human fibroblasts from old donors are representative of aging in vivo.

    “Altogether, these data show the existence of a positive correlation between senescence and the expression levels of β3 subunit and different regulators of the TGF-β pathway in aging.”
4 of 4

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Authors
Rapisarda, V., Borghesan, M., Miguela, V., Encheva, V., Snijders, A. P., Lujambio, A., & O’Loghlen, A.
Affiliations
  • Queen Mary University of London (GB)
  • The Francis Crick Institute (GB)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
O’Loghlen, Ana
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2017-03
Volume
18
Issue
10
Pages
2480-2493
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2017.02.012
PMC
PMC5357738
OpenAlex
W2594683399
Cited by
190
References
49
Citations by year
2026: 22 · 2025: 22 · 2024: 23 · 2023: 30 · 2022: 27 · 2021: 20 · 2020: 13 · 2019: 17 · 2018: 12 · 2017: 4
FWCI
8.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, other-oa)
Funders
  • Biotechnology and Biological Sciences Research Council (BB/P000223/1)
  • Queen Mary University of London
  • Medical Research Council (MR/K501372/1)
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
CD61, cellular senescence, TGF-beta signaling, CBX7, Polycomb group proteins, oncogene-induced senescence, therapy-induced senescence, senescence-associated secretory phenotype, cilengitide, fibroblasts, aging
MeSH terms
Aged, 80 and over, Aging, Animals, Cell Line, Cells, Cultured, Child, Extracellular Matrix, Fibroblasts, Humans, Isotope Labeling, RNA, Messenger, Signal Transduction, Up-Regulation, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Cellular Senescence, Protein Subunits, Integrin beta3, Cyclin-Dependent Kinase Inhibitor p21, Mice, Polycomb Repressive Complex 1

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

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