The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
Open accessAbstract
Transcriptional control of cell senescence: Senescent cells that have stopped proliferating secrete molecules that influence the cells around them. Prevention of this senescence-activated secretory phenotype seems to slow organismal aging. Kang et al. explored the regulatory process behind cell senescence and found that DNA damage led to stabilization of the transcription factor GATA4 (see the Perspective by Cassidy and Narita). Increased activity of GATA4 in senescent cells stimulated genes encoding secreted factors. GATA4 also accumulates in the brains of aging mice or humans. Science , this issue 10.1126/science.aaa5612 ; see also p. 1448
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- Findingown data
Depletion of the autophagic adaptor p62 increases GATA4 protein abundance.
“depletion of the autophagic adaptor p62 increased the abundance of GATA4 protein (Fig. 2F).”
Quote in the paperSubstantial claim - Findingown data
Depletion of ATG5 or ATG7 increases GATA4 protein abundance.
“depletion of the autophagy components ATG5 or ATG7 also increased the abundance of GATA4 protein (Fig. 2E).”
Quote in the paperSubstantial claim - Findingown data
Inhibiting NF-κB only partially reduces miR-146a reporter activity in senescent cells.
“NF-κB inhibition only partially decreased reporter activity in senescent cells (fig. S1D).”
Quote in the paperNot a substantial claim - Findingown data
p62 depletion induces senescence more effectively than depletion of ATG7 or ATG5 under normal conditions.
“p62 depletion induced senescence even more effectively than did depletion of the core autophagy regulators ATG7 or ATG5 under normal conditions (fig. S4D).”
Quote in the paperSubstantial claim - Findingcitation
The miR-146a promoter contains two evolutionarily conserved regions, ECR1 and ECR2.
“Using the Evolutionarily Conserved Regions browser (35), we found that the miR-146a promoter contains two evolutionarily conserved regions, ECR1 and ECR2.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Ovcharenko I Nobrega MA Loots GG Stubbs L ECR Browser: A tool for visualizing and accessing data from comparisons of multiple vertebrate genomes Nucleic Acids Res 32 W280 W286 2004 10.1093/nar/gkh355 15215395 PMC441493 source
Not checked in the free run.
- Findingown data
Ectopic GATA4 expression induces senescence in BJ and IMR-90 human fibroblasts, as shown by increased SA-β-Gal activity and decreased BrdU incorporation.
“Ectopic expression of GATA4 induced senescence in human foreskin fibroblasts (strain BJ; Fig. 1C) and IMR-90 fibroblasts (fig. S3, A and B), as shown by increased senescence-associated β-galactosidase (SA-β-Gal) activity and decreased 5-bromo-2′-deoxyuridine (BrdU) incorporation.”
Quote in the paperSubstantial claim - Findingown data
The increase in GATA4 is primarily due to increased protein stability, as measured by cycloheximide treatment and global protein stability profiling.
“This increase was primarily due to increased protein stability, as indicated by the measurement of protein stability in the presence of cycloheximide (Fig. 2B) and by global protein stability profiling (40) (fig. S4A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Yen HC Xu Q Chou DM Zhao Z Elledge SJ Global protein stability profiling in mammalian cells Science 322 918 923 2008 18988847 source
Not checked in the free run.
- Findingown data
GATA4 protein is stabilized by lysosomal inhibitors that block autophagy, including bafilomycin A1 and E64d plus pepstatin.
“GATA4 protein was stabilized in cells treated with distinct lysosomal inhibitors known to block autophagy: bafilomycin A1 (a selective inhibitor of the vacuolar-type H+–adenosine triphosphatase) or E64d and pepstatin (lysosomal protease inhibitors) (Fig. 2, C and D).”
Quote in the paperSubstantial claim - Findingown data
A miR-146a promoter reporter increases in response to replicative exhaustion, ionizing radiation (12 Gy), and oncogenic RAS expression.
“Expression of this reporter construct was significantly increased in response to several senescence-inducing stimuli, including replicative exhaustion, ionizing radiation (IR; 12 Gy), and expression of oncogenic RAS (fig. S1B).”
Quote in the paperNot a substantial claim - Findingown data
ECR2 is critical for miR-146a reporter activity.
“ECR2 was critical for reporter activity (fig. S1C).”
Quote in the paperNot a substantial claim - Findingown data
Proteasome inhibition by MG-132 has no effect on GATA4 abundance.
“Inhibition of the proteasome by MG-132, a proteasome inhibitor, had no effect on GATA4 abundance”
Quote in the paperSubstantial claim - Findingown data
GATA4 is required for miR-146a reporter activation during senescence.
“Depletion of GATA4 with siRNAs showed that it was required for reporter activation during senescence (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
The GATA4-regulated gene set overlaps significantly with the replicative senescence gene set, with greater statistical significance for up-regulated genes (P = 2.46 × 10−40).
“Both up-regulated and down-regulated genes overlapped significantly, with greater statistical significance for the up-regulated genes (P = 2.46 × 10−40)”
Quote in the paperSubstantial claim - Findingown data
miR-146a is highly expressed in senescent but not nonsenescent human IMR-90 fibroblasts after replicative exhaustion.
“we induced senescence by replicative exhaustion and found miR-146a to be highly expressed by senescent but not nonsenescent cells (fig. S1A)”
Quote in the paperNot a substantial claim - Findingown data
GATA4 activation in response to a senescence-inducing dose of IR remains intact in cells deficient in p53 or p53 and Rb.
“GATA4 activation in response to a senescence-inducing dose of IR remained intact in cells deficient in p53 or p53 and Rb (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
Activation of SASP-associated genes is transmitted to cells lacking GATA4 induction by conditioned medium from GATA4-induced cells.
“activation of SASP-associated genes was transmitted to cells lacking GATA4 induction by conditioned medium from GATA4-induced cells (fig. S5C).”
Quote in the paperSubstantial claim - Findingcitation
GATA4 induces expression of TRAF3IP2, an E3 ubiquitin ligase for TRAF6.
“GATA4 induced the expression of TRAF3IP2, an E3 ubiquitin ligase for TRAF6 (51) (Fig. 4C)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Liu C Act1, a U-box E3 ubiquitin ligase for IL-17 signaling Sci Signal 2 ra63 2009 10.1126/scisignal.2000382 19825828 PMC3182834 source
Not checked in the free run.
- Findingown data
There is a significant spatial correlation between GATA4 and p16INK4a in oligodendrocytes, pyramidal neurons, and astrocytes from older humans.
“we found a significant spatial correlation between GATA4 and p16INK4a in oligodendrocytes, pyramidal neurons, and astrocytes from older humans”
Quote in the paperSubstantial claim - Findingown data
TRAF3IP2 depletion partially blocks GATA4-induced senescence, as determined by SA-β-Gal activity.
“TRAF3IP2 depletion also partially blocked GATA4-induced senescence, as determined from SA-β-Gal activity (Fig. 4F).”
Quote in the paperSubstantial claim - Findingown data
Ectopic TRAF3IP2 together with IL1A is still not sufficient to induce SA-β-Gal activity, unlike GATA4.
“Moreover, ectopic expression of TRAF3IP2 together with IL1A was still not sufficient to induce SA-β-Gal activity, in contrast to that of GATA4 (fig. S6B).”
Quote in the paperSubstantial claim - Findingown data
Depletion of IL1A reduces GATA4 activation of NF-κB, as assessed by SASP gene expression.
“depletion of IL1A reduced GATA4 activation of NF-κB, as assessed by the expression of SASP genes (fig. S5B).”
Quote in the paperSubstantial claim - Findingown data
TRAF3IP2 depletion partially blocks GATA4 activation of NF-κB, as assessed by SASP gene expression.
“TRAF3IP2 depletion partially blocked GATA4 activation of NF-κB, as assessed by the expression of SASP genes (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data
RELA depletion inhibits expression of SASP genes in response to GATA4.
“RELA depletion inhibited the expression of genes associated with the SASP in response to GATA4 (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
GATA4 depletion suppresses expression of several SASP genes during establishment of senescence.
“depletion of GATA4 suppressed the expression of several SASP genes during the establishment of senescence (Fig. 3D)”
Quote in the paperSubstantial claim - Findingcitation
Among GATA4-regulated senescence-associated genes are SASP genes including IL6, IL8, CXCL1, GM-CSF, and ECM proteases and inhibitors.
“Among the GATA4-regulated, senescence-associated genes, we found several SASP genes, including those encoding IL6, IL8, C-X-C motif ligand 1 (CXCL1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and extracellular matrix (ECM) proteases and inhibitors (7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Coppé JP Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor PLOS Biol 6 e301 2008 10.1371/journal.pbio.0060301 PMC2592359 19053174 source
Not checked in the free run.
- Findingown data
Inhibition of the DDR regulators ATM and ATR suppresses activation of the GATA4 pathway during senescence.
“inhibition of the DDR regulators ATM (ataxia telan-giectasia mutated) and ATR (ataxia telangiectasia and Rad3–related) suppressed activation of the GATA4 pathway during senescence (Fig. 5F).”
Quote in the paperSubstantial claim - Findingown data
Aged but not young mouse livers show NF-κB activation, as determined by RELA phosphorylation.
“aged but not young mouse livers showed NF-κB activation, as determined by RELA phosphorylation, consistent with our cell culture results (Fig. 6C).”
Quote in the paperSubstantial claim - Findingcitation
PML and YPEL3 are among GATA4-induced genes.
“previously identified regulators of senescence, such as promyelocytic leukemia protein (PML) and yippee-like 3 (YPEL3), are among GATA4-induced genes (fig. S6D) (53).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] Purvis JE p53 dynamics control cell fate Science 336 1440 1444 2012 10.1126/science.1218351 22700930 PMC4162876 source
Not checked in the free run.
- Findingown data
RELA depletion almost completely blocks activation of SASP genes by GATA4, with the exception of IL1A.
“RELA depletion almost completely blocked the activation of SASP genes by GATA4, with the exception of IL1A (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
Ectopic TRAF3IP2 partially rescues the reduced SASP caused by GATA4 depletion in IR-induced senescent cells.
“ectopic expression of TRAF3IP2 partially rescued the reduced SASP caused by GATA4 depletion in IR-induced senescent cells (Fig. 4E).”
Quote in the paperSubstantial claim - Findingown data
The effects of GATA4 on senescence, measured by SA-β-Gal activity, are independent of p53 and the p16INK4a/Rb pathway in cells depleted of p53 or p53 and Rb by shRNAs or HPV E6/E7 expression.
“The effects ofGATA4 on senescence (SA-β-Gal activity) were independent of p53 and the p16INK4a/Rb pathway, as shown in cells depleted of p53 or p53 and Rb by shRNAs or expression of HPV E6 and E7 proteins (Fig. 5, A and B).”
Quote in the paperSubstantial claim - Findingown data
Gata4 abundance increases in the skin and liver of irradiated mice.
“The abundance of Gata4 increased in response to senescence-inducing amounts of IR in the skin and liver (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
Ectopic GATA4 expression induces expression of SASP-associated genes by RT-qPCR.
“We confirmed that ectopic expression of GATA4 induces the expression of genes associated with the SASP by reverse transcription qPCR (RT-qPCR) (Fig. 3C).”
Quote in the paperSubstantial claim - Interpretationreasoning
Senescence-inducing stimuli cause GATA4 to escape selective autophagy.
“senescence-inducing stimuli cause GATA4 to escape selective autophagy.”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 contributes to activation of the miR-146a promoter in senescent cells.
“These results indicate that GATA4 contributes to activation of the miR-146a promoter in senescent cells.”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 might activate a major portion of senescence-associated genes.
“These results suggest that GATA4 might activate a major portion of senescence-associated genes.”
Quote in the paperSubstantial claim - Interpretationown data
Transcription factors other than NF-κB also contribute to senescence-dependent activation of the miR-146a reporter.
“These results indicate that other transcription factors also contribute to senescence-dependent activation of the miR-146a reporter.”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 is a positive regulator of senescence.
“These data indicate that GATA4 is a positive regulator of senescence.”
Quote in the paperSubstantial claim - Interpretationown data
Degradation of GATA4 by selective autophagy is relieved in cells responding to senescence-inducing signals, contributing to growth arrest and accumulation of senescence markers.
“Degradation of GATA4 by selective autophagy is relieved in cells responding to senescence-inducing signals, which contributes to growth arrest and accumulation of senescence markers.”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 controls many SASP genes.
“indicating that GATA4 indeed controls many SASP genes.”
Quote in the paperSubstantial claim - Interpretationreasoning
GATA4 regulates cellular senescence in part through its effect on the SASP.
“This role of GATA4 in regulating cellular senescence operates in part through its effect on the SASP.”
Quote in the paperSubstantial claim - Interpretationown data
The GATA4 pathway that regulates senescent phenotypes is conserved in mice.
“Thus, the GATA4 pathway that regulates senescent phenotypes is conserved in mice.”
Quote in the paperSubstantial claim - Interpretationcitation
The GATA4-miR-146a-NF-κB circuit forms an incoherent type 1 feedforward loop that could limit the extent of the inflammatory response after the initial burst of SASP gene expression.
“This GATA4–miR-146a–NF-κB circuit forms an incoherent type 1 feedforward loop (60) that, after the initial burst of SASP gene expression, could limit the extent of the inflammatory response.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] Hart Y Alon U The utility of paradoxical components in biological circuits Mol Cell 49 213 221 2013 10.1016/j.molcel.2013.01.004 23352242 source
Not checked in the free run.
- Interpretationown data
GATA4 accumulates during DNA damage-induced senescence in vivo.
“Thus, GATA4 accumulates during DNA damage–induced senescence in vivo.”
Quote in the paperSubstantial claim - Interpretationreasoning
GATA4 might indirectly regulate other senescent phenotypes, notably growth arrest, through the SASP.
“GATA4 might indirectly regulate other senescent phenotypes, notably growth arrest, through the SASP.”
Quote in the paperNot a substantial claim - Interpretationown data
GATA4 acts at least in part through TRAF3IP2 and IL1A to activate NF-κB in activating the SASP.
“Thus, GATA4 appears to act, at least in part, through TRAF3IP2 and IL1A to activate NF-κB in activating the SASP.”
Quote in the paperSubstantial claim - Interpretationcitation
GATA4 activates expression of miR-146a, which dampens NF-κB activation.
“GATA4 also activates expression of miR-146a, which dampens the activation of NF-κB (17).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Demaria M An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA Dev Cell 31 722 733 2014 10.1016/j.devcel.2014.11.012 25499914 PMC4349629 source
Not checked in the free run.
- Interpretationown data
GATA4 functions independently of p53 and the p16INK4a/Rb pathway in regulating senescent phenotypes.
“Thus, GATA4 appears to function independently of p53 and the p16INK4a/Rb pathway in regulating senescent phenotypes”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 may contribute to cellular senescence and the resulting inflammation during mouse and human aging.
“Thus, GATA4 may contribute to cellular senescence and the resulting inflammation during mouse and human aging.”
Quote in the paperSubstantial claim - Interpretationown data
The DNA damage response acts upstream of the GATA4 pathway.
“which suggests that the DNA damage response (DDR) acts upstream of this pathway”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 acts upstream of NF-κB in regulating the SASP.
“these findings suggest that GATA4 acts upstream of NF-κB in regulating the SASP.”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 has a specific role in SASP regulation.
“These results support a specific role for GATA4 in SASP regulation.”
Quote in the paperSubstantial claim - Interpretationreasoning
The inflammatory response is not extinguished, as senescent cells maintain the SASP despite high miR-146a levels.
“However, it clearly does not extinguish the inflammatory response, as senescent cells maintain the SASP despite high levels of miR-146a.”
Quote in the paperSubstantial claim - Interpretationown data
GATA4 acts as an upstream regulator of NF-κB through TRAF3IP2 and IL1A to initiate and maintain NF-κB activity.
“In doing so, GATA4 acts as an upstream regulator of NF-κB through TRAF3IP2 and IL1A to initiate and maintain NF-κB activity (Fig. 5G).”
Quote in the paperSubstantial claim - Premisecitation
NF-κB has a crucial role in controlling the SASP.
“NF-κB has a crucial role in controlling the SASP (18, 19, 49) (Fig. 3D)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [18] Salminen A Kauppinen A Kaarniranta K Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP) Cell Signal 24 835 845 2012 10.1016/j.cellsig.2011.12.006 22182507 source
Not checked in the free run.
- cites [19] Freund A Patil CK Campisi J p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype EMBO J 30 1536 1548 2011 10.1038/emboj.2011.69 21399611 PMC3102277 source
Not checked in the free run.
- cites [49] Chien Y Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity Genes Dev 25 2125 2136 2011 10.1101/gad.17276711 21979375 PMC3205583 source
Not checked in the free run.
- Interpretationown data
Certain SASP factors such as IL6 and CXCL3 are resistant to TRAF3IP2 depletion, suggesting GATA4 regulates them in a TRAF3IP2-independent manner.
“certain SASP factors, such as IL6 and CXCL3, were resistant to TRAF3IP2 depletion; this result suggests that GATA4 regulates them in a TRAF3IP2-independent manner, either directly or indirectly through its other downstream targets.”
Quote in the paperSubstantial claim - Interpretationreasoning
IL1A might cooperate with TRAF3IP2 during GATA4-dependent production of the SASP.
“Thus, IL1A might cooperate with TRAF3IP2 during GATA4-dependent production of the SASP.”
Quote in the paperSubstantial claim - Interpretationreasoning
The GATA4 pathway that induces the SASP appears to be an independent branch of the DDR.
“Thus, the GATA4 pathway that induced the SASP appears to be an independent branch of the DDR.”
Quote in the paperSubstantial claim - Interpretationown data
The SASP may not be the only mechanism through which GATA4 regulates senescence.
“Thus, the SASP may not be the only mechanism through which GATA4 regulates senescence.”
Quote in the paperSubstantial claim - Interpretationnone given
The GATA4 pathway is completely independent of p53 and p16INK4a.
“More important, the GATA4 pathway is completely independent of p53 and p16INK4a.”
Quote in the paperNot a substantial claim
- May combine two claims. 27
- Classified as probably not a substantial claim. 20
May combine two claims.
Findingown dataExogenous and endogenous GATA4 physically interact with p62, and this interaction is reduced during senescence.
“Exogenously expressed and endogenous GATA4 physically interacted with p62, and the interaction was reduced during senescence (Fig. 2G and fig. S4B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataContinuous and transient autophagy inhibition increase GATA4 abundance similarly, but continuous inhibition fails to induce senescence.
“Continuous and transient inhibition of autophagy increased GATA4 abundance to similar extents, but continuous inhibition failed to induce senescence (Fig. 2I).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGATA4 depletion partially decreases IR-induced SA-β-Gal activity and delays replicative senescence.
“depletion of GATA4 with stably expressed short hairpin RNAs (shRNAs) partially decreased IR-induced SA-β-Gal activity (Fig. 1D and fig. S3C) and delayed replicative senescence (Fig. 1E).”
- Also stated in: § GATA4, a novel senescence regulator · plain
“We confirmed these results by CRISPR mutation of GATA4 (fig. S3D).”
Quote in the paperSubstantial claim- Also stated in: § GATA4, a novel senescence regulator · plain
May combine two claims.
Findingown dataGATA4-induced genes are enriched for immune response, inflammatory response, and response to wounding, whereas GATA4-repressed genes are enriched for cell cycle processes.
“Genes showing increased expression in response to GATA4 showed significant enrichment for the terms “immune response,” “inflammatory response,” and “response to wounding,” whereas genes with decreased expression were mostly enriched for biological processes related to the cell cycle”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGATA4 protein, but not mRNA, increases during IR-induced, oncogene-induced, and replicative senescence.
“abundance of the GATA4 protein, but not mRNA, increased during IR- and oncogene-induced senescence and replicative senescence (Fig. 2A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTransient inhibition of autophagy induces senescence more effectively than continuous inhibition, and this effect at least in part depends on GATA4.
“Transient inhibition of autophagy (GATA4 abundance high, autophagy on) induced senescence more effectively than did continuous inhibition (GATA4 abundance high, autophagy off); this effect, at least in part, depended on GATA4 (Fig. 2, H and I, and fig. S4C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong 13 candidate transcription factors, only GATA4 activated the miR-146a reporter; other GATA family members did not.
“Of 13 transcription factors selected, only GATA4, but not other GATA family members, activated the reporter (Fig. 1A and fig. S2, A and B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEven in nutlin-treated cells, IR activates GATA4 and NF-κB.
“Even in nutlin-treated cells, in which GATA4 was not initially activated, IR activated GATA4 and NF-κB (Fig. 5E)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGATA4 expression triggers NF-κB activation, and GATA4 depletion inhibits NF-κB activation during senescence.
“GATA4 expression triggered NF-κB activation, and GATA4 depletion inhibited NF-κB activation during senescence (Fig. 4B)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTRAF3IP2 expression alone is not sufficient to induce SA-β-Gal activity, despite activating SASP-associated genes.
“Unlike GATA4 expression, however, TRAF3IP2 expression alone was not sufficient to induce SA-β-Gal activity (fig. S6A), despite activating expression of a number of SASP-associated genes (fig. S6C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGATA4 abundance increases in prefrontal cortex samples from older humans, as does p16INK4a abundance.
“The abundance of GATA4 increased in prefrontal cortex samples from older humans, as did the abundance of p16INK4a (Fig. 6D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAged mice (22 months) show increased Gata4 accumulation in livers and kidneys relative to young mice (6 months), and this accumulation correlates with p16INK4a amounts.
“We examined young and old mice (age 6 months and 22 months, respectively) and found increased accumulation of Gata4 in the livers and kidneys of aged mice relative to the same organs of young animals; this accumulation correlated with the amounts of p16INK4a (Fig. 6C and fig. S6, E and F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn mouse embryonic fibroblasts induced to senesce by IR under physiological O2, Gata4 abundance increases and is required for induction of Gata4 target genes including Traf3ip2, Il6, Il1A, and Cxcl1.
“The abundance of Gata4 increased in response to senescence-inducing IR and was required for the induction of several Gata4 target genes, including those that encode Traf3ip2 and the SASP factors Il6, Il1A, and Cxcl1.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [56] Parrinello S Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts Nat Cell Biol 5 741 747 2003 10.1038/ncb1024 12855956 PMC4940195 source
Not checked in the free run.
- cites [57] Coppé JP A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen PLOS ONE 5 e9188 2010 10.1371/journal.pone.0009188 20169192 PMC2820538 source
Not checked in the free run.
May combine two claims.
Findingown dataNeither p53 activation by nutlin nor p16INK4a activation by Dox-induced expression is sufficient to activate GATA4.
“neither p53 activation by nutlin nor p16INK4a activation by Dox-induced expression was sufficient to activate GATA4 (Fig. 5D).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSASP factors can reinforce senescence growth arrest in an autocrine manner or transmit the senescence phenotype to neighboring cells in a paracrine manner.
“Depending on the physiological context, SASP factors can either reinforce senescence growth arrest in an autocrine manner or relay the senescence phenotype to surrounding cells in a paracrine manner (11–13).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [11] Kuilman T Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network Cell 133 1019 1031 2008 10.1016/j.cell.2008.03.039 18555778 source
Not checked in the free run.
- cites [12] Wajapeyee N Serra RW Zhu X Mahalingam M Green MR Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7 Cell 132 363 374 2008 10.1016/j.cell.2007.12.032 18267069 PMC2266096 source
Not checked in the free run.
- cites [13] Acosta JC A complex secretory program orchestrated by the inflammasome controls paracrine senescence Nat Cell Biol 15 978 990 2013 10.1038/ncb2784 23770676 PMC3732483 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSenescent cells express and secrete many proinflammatory cytokines, chemokines, growth factors, and proteases, a set collectively called the senescence-associated secretory phenotype (SASP).
“senescent cells display extensive changes in gene expression, including the expression and secretion of many proinflammatory cytokines, chemokines, growth factors, and proteases; collectively these features are termed the senescence-associated secretory phenotype (SASP) (2, 7–10).”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [2] Campisi J Aging, cellular senescence, and cancer Annu Rev Physiol 75 685 705 2013 10.1146/annurev-physiol-030212-183653 23140366 PMC4166529 source
Not checked in the free run.
- cites [7] Coppé JP Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor PLOS Biol 6 e301 2008 10.1371/journal.pbio.0060301 PMC2592359 19053174 source
Not checked in the free run.
- cites [8] Kuilman T Peeper DS Senescence-messaging secretome: SMS-ing cellular stress Nat Rev Cancer 9 81 94 2009 10.1038/nrc2560 19132009 source
Not checked in the free run.
- cites [9] Coppé JP Desprez PY Krtolica A Campisi J The senescence-associated secretory phenotype: The dark side of tumor suppression Annu Rev Pathol 5 99 118 2010 10.1146/annurev-pathol-121808-102144 20078217 PMC4166495 source
Not checked in the free run.
- cites [10] Tchkonia T Zhu Y van Deursen J Campisi J Kirkland JL Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities J Clin Invest 123 966 972 2013 10.1172/JCI64098 23454759 PMC3582125 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFactors secreted by senescent cells can stimulate the immune system to suppress tumorigenesis and promote repair of damaged tissues.
“these secreted factors can stimulate the immune system to both suppress tumorigenesis and promote optimal repair of damaged tissues when senescent cells are removed after their beneficial actions (15–17).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [15] Krizhanovsky V Senescence of activated stellate cells limits liver fibrosis Cell 134 657 667 2008 10.1016/j.cell.2008.06.049 18724938 PMC3073300 source
Not checked in the free run.
- cites [16] Lujambio A Non-cell-autonomous tumor suppression by p53 Cell 153 449 460 2013 10.1016/j.cell.2013.03.020 23562644 PMC3702034 source
Not checked in the free run.
- cites [17] Demaria M An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA Dev Cell 31 722 733 2014 10.1016/j.devcel.2014.11.012 25499914 PMC4349629 source
Not checked in the free run.
May combine two claims.
PremisecitationECR2 contains a putative NF-κB binding site, and NF-κB is known to regulate miR-146a.
“Because ECR2 has a putative NF-κB binding site and NF-κB is known to regulate miR-146a (36)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Taganov KD Boldin MP Chang KJ Baltimore D NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses Proc Natl Acad Sci USA 103 12481 12486 2006 10.1073/pnas.0605298103 16885212 PMC1567904 source
Not checked in the free run.
May combine two claims.
Interpretationown dataSelective autophagy for GATA4 acts as a negative senescence regulator, whereas general autophagy acts as a positive regulator.
“Hence, selective autophagy for GATA4 may be a negative senescence regulator, whereas general autophagy is a positive regulator of senescence.”
- Also stated in: § Selective autophagy suppresses GATA4 and senescence · hedged
“Thus, selective autophagy for GATA4 appears to function as an anti-senescence mechanism, whereas general autophagy functions as a pro-senescence mechanism.”
Quote in the paperSubstantial claim- Also stated in: § Selective autophagy suppresses GATA4 and senescence · hedged
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAutophagy has been implicated in establishing the SASP through the TOR autophagy spatial coupling compartment (TASCC).
“macro-autophagy (hereafter referred to as autophagy)—a tightly regulated major lysosomal degradation pathway (27–30)—has been implicated in establishing the SASP through the target of rapamycin (TOR) autophagy spatial coupling compartment (TASCC).”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [27] Mizushima N Levine B Cuervo AM Klionsky DJ Autophagy fights disease through cellular self-digestion Nature 451 1069 1075 2008 10.1038/nature06639 18305538 PMC2670399 source
Not checked in the free run.
- cites [28] Kroemer G Mariño G Levine B Autophagy and the integrated stress response Mol Cell 40 280 293 2010 10.1016/j.molcel.2010.09.023 20965422 PMC3127250 source
Not checked in the free run.
- cites [29] Choi AM Ryter SW Levine B Autophagy in human health and disease N Engl J Med 368 651 662 2013 10.1056/NEJMra1205406 23406030 source
Not checked in the free run.
- cites [30] Klionsky DJ Codogno P The mechanism and physiological function of macroautophagy J Innate Immun 5 427 433 2013 10.1159/000351979 23774579 PMC6741458 source
Not checked in the free run.
- cites [31] Young AR Autophagy mediates the mitotic senescence transition Genes Dev 23 798 803 2009 10.1101/gad.519709 19279323 PMC2666340 source
Not checked in the free run.
- cites [32] Narita M Spatial coupling of mTOR and autophagy augments secretory phenotypes Science 332 966 970 2011 10.1126/science.1205407 21512002 PMC3426290 source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationreasoningSelective autophagy may prevent senescence by suppressing positive senescence regulators such as GATA4.
“Selective autophagy might prevent senescence by suppressing positive senescence regulators such as GATA4.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningGeneral autophagy may be activated after senescence stimuli and contributes to establishing senescence.
“Subsequently, general autophagy may be activated, which then contributes to establishment of senescence.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe autophagy-lysosome pathway, not the ubiquitin-proteasome pathway, regulates GATA4.
“These findings suggest the autophagy-lysosome pathway, not the ubiquitin-proteasome pathway, regulates GATA4.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe SASP does not depend on p53 or p16INK4a, suggesting that it is controlled by a separate branch of the senescence regulatory network.
“the SASP does not depend on either p53 or p16INK4a, which suggests that it is controlled by an independent branch of the senescence regulatory network (2, 10, 20, 26).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [2] Campisi J Aging, cellular senescence, and cancer Annu Rev Physiol 75 685 705 2013 10.1146/annurev-physiol-030212-183653 23140366 PMC4166529 source
Not checked in the free run.
- cites [10] Tchkonia T Zhu Y van Deursen J Campisi J Kirkland JL Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities J Clin Invest 123 966 972 2013 10.1172/JCI64098 23454759 PMC3582125 source
Not checked in the free run.
- cites [20] Rodier F Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion Nat Cell Biol 11 973 979 2009 10.1038/ncb1909 19597488 PMC2743561 source
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- cites [26] Coppé JP Tumor suppressor and aging biomarker p16 (INK4a) induces cellular senescence without the associated inflammatory secretory phenotype J Biol Chem 286 36396 36403 2011 10.1074/jbc.M111.257071 21880712 PMC3196093 source
Not checked in the free run.
May combine two claims.
Interpretationown dataGATA4 is targeted for autophagic degradation through p62 under normal conditions but becomes stabilized during senescence, possibly through reduced p62 association.
“Thus, GATA4 appears to be targeted for autophagic degradation through its association with p62 under normal conditions but becomes stabilized during senescence, possibly through reduced association with p62.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOther findings indicate that inhibiting autophagy promotes senescence in some contexts.
“other findings indicate that autophagy inhibition promotes senescence in some contexts (33).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Gewirtz DA Autophagy and senescence: A partnership in search of definition Autophagy 9 808 812 2013 10.4161/auto.23922 23422284 PMC3669198 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSenescent cells can stimulate adjacent premalignant and malignant cells to proliferate and form tumors.
“Senescent cells can also stimulate adjacent premalignant and malignant cells to proliferate and form tumors (14).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Krtolica A Parrinello S Lockett S Desprez PY Campisi J Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging Proc Natl Acad Sci USA 98 12072 12077 2001 10.1073/pnas.211053698 11593017 PMC59769 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFactors secreted by senescent cells may promote chronic inflammation, which is thought to be a major factor in many age-related diseases.
“factors secreted by senescent cells may directly or indirectly promote chronic inflammation that is thought to be a major factor in many, if not all, age-related diseases (2, 9, 10).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [2] Campisi J Aging, cellular senescence, and cancer Annu Rev Physiol 75 685 705 2013 10.1146/annurev-physiol-030212-183653 23140366 PMC4166529 source
Not checked in the free run.
- cites [9] Coppé JP Desprez PY Krtolica A Campisi J The senescence-associated secretory phenotype: The dark side of tumor suppression Annu Rev Pathol 5 99 118 2010 10.1146/annurev-pathol-121808-102144 20078217 PMC4166495 source
Not checked in the free run.
- cites [10] Tchkonia T Zhu Y van Deursen J Campisi J Kirkland JL Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities J Clin Invest 123 966 972 2013 10.1172/JCI64098 23454759 PMC3582125 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGATA4 is a zinc finger transcription factor essential for development of several organs, including heart, testis, foregut, liver, and ventral pancreas.
“GATA4 is a zinc finger transcription factor essential for the development of various organs, including heart, testis, foregut, liver, and ventral pancreas (37).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Viger RS Guittot SM Anttonen M Wilson DB Heikinheimo M Role of the GATA family of transcription factors in endocrine development, function, and disease Mol Endocrinol 22 781 798 2008 10.1210/me.2007-0513 18174356 PMC2276466 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGATA4 is frequently silenced in lung, colon, prostate, ovarian, and breast cancer.
“GATA4 is frequently silenced in lung, colon, prostate, ovarian, and breast cancer (38, 39).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [38] Zheng R Blobel GA GATA transcription factors and cancer Genes Cancer 1 1178 1188 2010 10.1177/1947601911404223 21779441 PMC3092280 source
Not checked in the free run.
- cites [39] Agnihotri S A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas J Exp Med 208 689 702 2011 10.1084/jem.20102099 21464220 PMC3135351 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigh miR-146a expression in senescent cells has also been reported for human foreskin fibroblasts (HCA2).
“a result also reported for human foreskin fibroblasts (HCA2) (34).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Bhaumik D MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8 Aging 1 402 411 2009 20148189 PMC2818025 source
Not checked in the free run.
May combine two claims.
Interpretationown dataIn response to IR, senescent phenotypes depend on the DDR signaling kinases ATM and ATR, as does senescence-associated expression of p53 and p16INK4a.
“In response to IR, these senescent phenotypes depend on the DDR signaling kinases ATM and ATR, as does senescence-associated expression of p53 and p16INK4a.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationIL1A is thought to form a feedforward activation loop with NF-κB in SASP regulation.
“IL1A, a SASP component, is thought to form a feedforward activation loop with NF-κB in SASP regulation (13, 52).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Acosta JC A complex secretory program orchestrated by the inflammasome controls paracrine senescence Nat Cell Biol 15 978 990 2013 10.1038/ncb2784 23770676 PMC3732483 source
Not checked in the free run.
- cites [52] Orjalo AV Bhaumik D Gengler BK Scott GK Campisi J Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network Proc Natl Acad Sci USA 106 17031 17036 2009 10.1073/pnas.0905299106 19805069 PMC2761322 source
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May combine two claims.
InterpretationcitationAutophagy is both a negative and a positive regulator of senescence, resolving apparently contradictory reports in the literature.
“Our results indicate that autophagy is both a negative and a positive regulator of senescence, resolving apparently contradictory reports in the literature (31–33, 44).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [31] Young AR Autophagy mediates the mitotic senescence transition Genes Dev 23 798 803 2009 10.1101/gad.519709 19279323 PMC2666340 source
Not checked in the free run.
- cites [32] Narita M Spatial coupling of mTOR and autophagy augments secretory phenotypes Science 332 966 970 2011 10.1126/science.1205407 21512002 PMC3426290 source
Not checked in the free run.
- cites [33] Gewirtz DA Autophagy and senescence: A partnership in search of definition Autophagy 9 808 812 2013 10.4161/auto.23922 23422284 PMC3669198 source
Not checked in the free run.
- cites [44] Ivanov A Lysosome-mediated processing of chromatin in senescence J Cell Biol 202 129 143 2013 10.1083/jcb.201212110 23816621 PMC3704985 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe GATA4 pathway is independent of p53 and p16INK4a, establishing a new branch of the DDR pathway.
“However, the GATA4 pathway is independent of p53 and p16INK4a, thus establishing a new branch of the DDR pathway.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThis pathway can positively contribute to normal development and wound healing.
“This pathway can positively contribute to normal development and wound healing (15, 17, 61, 62).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [15] Krizhanovsky V Senescence of activated stellate cells limits liver fibrosis Cell 134 657 667 2008 10.1016/j.cell.2008.06.049 18724938 PMC3073300 source
Not checked in the free run.
- cites [17] Demaria M An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA Dev Cell 31 722 733 2014 10.1016/j.devcel.2014.11.012 25499914 PMC4349629 source
Not checked in the free run.
- cites [61] Muñoz-Espín D Programmed cell senescence during mammalian embryonic development Cell 155 1104 1118 2013 10.1016/j.cell.2013.10.019 24238962 source
Not checked in the free run.
- cites [62] Storer M Senescence is a developmental mechanism that contributes to embryonic growth and patterning Cell 155 1119 1130 2013 10.1016/j.cell.2013.10.041 24238961 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataQuantitative RT-qPCR measurements were run in triplicate.
“Quantitative RT-qPCR was performed in triplicate using the Gene Expression Assay (Applied Biosystems) on an Applied Biosystems Fast 7500 machine with GAPDH as an endogenous normalization control.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataGATA4 is a key regulator of crucial senescent phenotypes and connects autophagy and the DDR to senescence and inflammation through IL1A and TRAF3IP2 activation of NF-κB.
“Together, our results indicate that GATA4 is a key regulator of crucial senescent phenotypes, and connects autophagy and the DDR to senescence and inflammation through IL1A and TRAF3IP2 activation of NF-κB.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataCRISPR targeting of GATA4 was verified by PCR and Sanger sequencing of the targeted genomic region.
“GATA4 CRISPR targeting was confirmed by PCR and Sanger sequencing of targeting genomic region with following primers: Fwd, AGCCCCGGT-CAGTTCTCCTCTCAGGAGAA; Rev, TAAGGTAGG-AGGTAGAGGTCATGCTTTCC.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe GATA4-regulated mRNA-seq analysis used three independent experiments, yielding six samples in total.
“Three independent experiments were performed, giving a total of six samples for mRNA-seq analysis.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationAccumulation of senescent cells as organisms age is thought to promote aging-related phenotypes and diseases, including cancer and neurodegeneration, in a cell-nonautonomous manner.
“the accumulation of senescent cells as organisms age is thought to promote aging-related phenotypes and aging-associated diseases, including cancer and neurodegeneration, in a cell-nonautonomous manner (2, 3, 10).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2] Campisi J Aging, cellular senescence, and cancer Annu Rev Physiol 75 685 705 2013 10.1146/annurev-physiol-030212-183653 23140366 PMC4166529 source
Not checked in the free run.
- cites [3] López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging Cell 153 1194 1217 2013 10.1016/j.cell.2013.05.039 23746838 PMC3836174 source
Not checked in the free run.
- cites [10] Tchkonia T Zhu Y van Deursen J Campisi J Kirkland JL Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities J Clin Invest 123 966 972 2013 10.1172/JCI64098 23454759 PMC3582125 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe investigator who analyzed the human brain immunofluorescence was blinded to each sample's origin and diagnosis.
“The investigator was blinded to sample origin or diagnosis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenImmunofluorescence images from the prefrontal cortex were collected randomly for quantification.
“Images were randomly acquired in the prefrontal cortex for quantification of immunofluorescence.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataUsing multiple antibodies against GATA4 and p16 in immunofluorescence produced consistent conclusions.
“Analysis of GATA4 and p16 expression by immunofluorescence with antibodies obtained from these sources led to similar conclusions.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Knowledge about the regulatory network that receives senescence signals and initiates the senescence response is still lacking.
“However, knowledge about the regulatory network that receives senescence signals and initiates the senescence response is still lacking.”
The paper relies on this without support.
How the NF-κB inflammatory response becomes activated under senescence-inducing conditions is not known.
“How the NF-κB inflammatory response becomes activated under senescence-inducing conditions is not known.”
The paper relies on this without support.
Little is known about how the SASP is regulated beyond NF-κB and the classical inflammation regulators associated with NF-κB activity.
“Despite the wide range of biological activities attributed to the SASP, little is known about how it is regulated beyond the activation of NF-κB and the classical regulators of inflammation associated with NF-κB activity, such as CCAAT/ enhancer-binding protein β (C/EBPβ), interleukin-1α (IL-1α), and p38 mitogen-activated protein kinase (p38 MAPK) (2, 18–20).”
The paper relies on this without support.
The relationship between autophagy and senescence is unclear.
“Thus, the relationship between autophagy and senescence is unclear.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
GATA4 acts as a molecular link between DDR signalling and subsequent NF-κB activation for full SASP establishment, although its regulation of NF-κB is indirect through increased IL-1α expression and secretion.
“Because GATA4 levels increase following DDR activation and in senescent cells, it was proposed that GATA4 acts as the molecular link between DDR signalling and the subsequent NF-κB activation for full SASP establishment95,96, although GATA4 regulation of the NF-κB pathway happens indirectly through increased expression and secretion of IL-1α, an upstream regulator of NF-κB97”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [95]
The sections ‘GATA4, a new branch of the senescence regulatory pathway’ and ‘GATA4 regulates NF-κB’ place GATA4 downstream of DDR signalling and upstream of NF-κB in SASP regulation. The latter section identifies IL1A as one mediator, but also identifies TRAF3IP2; it does not specifically show increased IL1A secretion. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSenescence can act as a potent anti-tumor mechanism by preventing proliferation of potentially cancerous cells.
“Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kang et al., 2015
Stabilized GATA-4 enhances SASP via TRAF3IP2 and IL-1A mediated NF-κB activation and establishes GATA4 as a separate branch of senescence regulatory pathway independent of p53 and p16INK4A for inducing SASP.
“The stabilized GATA-4 enhances SASP via TRAF3IP2 and IL-1A mediated NF-κB activation and establishes GATA4 as a separate branch of the senescence regulatory pathway independent of p53 and p16INK4A for inducing SASP (Kang et al., 2015).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kang et al., 2015
In normal cells, GATA-4 bound to p62 is degraded by selective autophagy whereas induction of senescence in DNA damaged cells leads to suppression of autophagy and stabilization of GATA-4.
“In normal cells, GATA-4 bound to autophagy regulator, p62, is degraded by selective autophagy whereas induction of senescence in DNA damaged cells leads to suppression of autophagy and hence stabilization of GATA-4.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kang et al., 2015
DNA damage can also lead to NF-κB activation via stabilization of GATA4.
“DNA damage can also lead to NF-κB activation via stabilization of GATA4 (Kang et al., 2015).”
From DNA damage-how and why we age? (2021) · cites this paper as Kang et al., 2015
IL-1α is the key driver of the SASP, with upstream expression controlled in part by ATM/ATR-mediated liberation of GATA4 from p62-directed autophagy and/or an mTORC1-dependent pathway.
“IL-1α is the key driver of the SASP 79,80 , with upstream expression controlled in part by ATM/ATRmediated liberation of GATA4 from p62-directed autophagy 81 and/or an mTORC1-dependent pathway 82 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [81]
GATA4 accumulates in senescent cells and induces the expression of IL-1α and TRAF3IP2 that activate NF-κB to initiate and amplify the SASP response.
“GATA4 accumulates in senescent cells and induces the expression of IL-1α and TRAF3IP2 (an E3 ubiquitin ligase) that activate NF-κB to initiate and amplify the SASP response [160].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [160]
GATA4 induces the SASP through a distinct p53- and p16-independent branch of the DDR signaling pathway to facilitate senescence.
“GATA4 induces the SASP through a distinct (p53- and p16-independent) branch of the DDR signaling pathway to facilitate senescence [160].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [160]
Under basal conditions, SQSTM1/p62 interacts with GATA4 and mediates its degradation by selective autophagy.
“Under basal conditions, the autophagic adaptor SQSTM1/p62 interacts with GATA4 and mediates its degradation by selective autophagy.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [160]
Selective autophagy of GATA4, which accumulates during senescence induction, can prevent senescence.
“Conversely, selective autophagy, for instance of GATA4 that accumulates during senescence induction [160], can prevent senescence [160,246].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [160]
Upon irradiation or oncogene hyperactivation, ATM and ATR activation suppresses selective autophagy by promoting GATA4 dissociation from SQSTM1/p62, resulting in GATA4 stabilization.
“Conversely, upon irradiation or oncogene hyperactivation, activation of ATM and ATR suppresses selective autophagy by promoting GATA4 dissociation from SQSTM1/p62, resulting in GATA4 stabilization.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [160]
GATA4 initiates synthesis of SASP factors via NF-κB activation, partly mediated by IL-1α production.
“Then, GATA4 initiates the synthesis of SASP factors via NF-κB activation, partly mediated by IL-1 α production [160].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [160]
GATA4 activates NF-kB to initiate SASP and facilitate senescence progression.
“GATA4 in turn activates the NF-kB transcription factor to initiate SASP and facilitate senescence progression.”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [76]
Proteins known to turnover through autophagic degradation accumulate in senescent cells, including GATA4.
“Furthermore, proteins known to turnover through autophagic degradation accumulate in senescent cells, including the GATA4 transcription factor, an important regulator of SASP [76].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [76]
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Self-citationCellular Senescence in Aging Primates
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“Among the GATA4-regulated, senescenceassociated genes, we found several SASP genes, including those encoding IL6, IL8, C-X-C motif ligand 1 (CXCL1), granulocyte-macrophage colonystimulating factor (GM-CSF), and extracellular matrix (ECM) proteases and inhibitors (7).”
BackgroundSelf-citationGATA Transcription Factors and Cancer
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Role of the GATA Family of Transcription Factors in Endocrine Development, Function, and Disease
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Act1, a U-box E3 Ubiquitin Ligase for IL-17 Signaling
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“To determine whether GATA4 responds to senescence induction in mice in vivo, we examined irradiated mice, which show senescent cells in multiple tissues (58).”
BackgroundSelf-citationAutophagy and senescence: A partnership in search of definition
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The Utility of Paradoxical Components in Biological Circuits
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A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas
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Cellular Senescence: Defining a Path Forward
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Self-citationAgeing as a risk factor for neurodegenerative disease
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Hallmarks of Cellular Senescence
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Cellular Senescence: Aging, Cancer, and Injury
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Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
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“On a molecular level, several transcription factors have been implicated in the up-regulation of SASP-genes including NF-κ B, C/EBP-β , p38 MAPK and GATA4 12, 13, 14, 15, 16.”
Senescence and the SASP: many therapeutic avenues
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“Increased stabilization of the transcription factor GATAbinding protein 4 (GATA4) connects the DDR with NFκB activation to induce the SASP (Kang et al. 2015).”
BackgroundCellular senescence and senolytics: the path to the clinic
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Cellular senescence drives age-dependent hepatic steatosis
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Mitochondrial dysfunction in cell senescence and aging
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Exploiting senescence for the treatment of cancer
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Unmasking senescence: context-dependent effects of SASP in cancer
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The senescence-associated secretory phenotype and its physiological and pathological implications
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Metabolic Control of Longevity
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The dynamic nature of senescence in cancer
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The senescence-associated secretory phenotype and its regulation
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Identification of senescent cells in the bone microenvironment
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Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis
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“Senescent Astrocytes and SASP Factors Are Elevated in Parkinsonian Substantia Nigra Pars Compacta Astrocytes expressing senescence markers increase in human brain tissue during normal aging (Kang et al., 2015) and further in affected brain regions of individuals with Alzheimer’s disease (AD) and amyotrophic lateral sc…”
Self-citationNOTCH1 mediates a switch between two distinct secretomes during senescence
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The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging
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Strategies for targeting senescent cells in human disease
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From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence
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Self-citationChronic inflammation and the hallmarks of aging
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BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
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“Consistent with this view, control of such amplifier genes may underlie the action of GATA4 on SASP during replicative senescence (31).”
InfluentialSenescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration
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Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link?
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“As an example, it has been suggested that selective autophagy may suppress senescence through the degradation of the pro-senescence factor GATA4 whilst senescence may indeed be promoted by general autophagy through the TASCC (Kang et al., 2015; Narita et al., 2011).”
BackgroundInfluentialMechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
DNA damage-how and why we age?
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Cellular senescence in renal ageing and disease
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Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice
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“(2019) proved that cortical neurons cultured in vitro for 26 days express a higher level of GATA4 transcription factor, which was shown to participate in the regulation of SASP factors expression (Kang et al., 2015).”
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Nuclear genomic instability and aging
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Autophagy and the hallmarks of aging
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- Authors
- Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., Lu, T., Yankner, B. A., Campisi, J., & Elledge, S. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Buck Institute for Research on Aging (US)
- Harvard University (US)
- Corresponding author
- Elledge, Stephen J.
- ORCID
- Venue
- Science
- Published
- 2015-09-25
- Volume
- 349
- Issue
- 6255
- Pages
- aaa5612-aaa5612
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4942138
- OpenAlex
- W1800944583
- Semantic Scholar
- 1c8d59d11fcdf222bbe3773e00513f264d268be0
- Cited by
- 982
- References
- 67
- Citations by year
- 2026: 64 · 2025: 103 · 2024: 99 · 2023: 91 · 2022: 125 · 2021: 117 · 2020: 94 · 2019: 90 · 2018: 72 · 2017: 70 · 2016: 53 · 2015: 3 · 2013: 1
- FWCI
- 48.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (GM44664, AG009909, AG017242, DP1OD006849, AG046174)
- HHMI
- American Cancer Society
- Damon Runyon Cancer Research Foundation
- Glenn Foundation for Medical Research
- American-Italian Cancer Foundation
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- GATA4, cellular senescence, senescence-associated secretory phenotype, DNA damage response, autophagy, p62, NF-κB, inflammation, ATM, ATR, protein stabilization, aging, brain aging, transcription factors
- MeSH terms
- Aging, Animals, Autophagy, Brain, Cell Cycle, Cells, Cultured, DNA Damage, Fibroblasts, Humans, Inflammation, Mice, Inbred C57BL, Phenotype, Promoter Regions, Genetic, Tumor Suppressor Protein p53, NF-kappa B, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Gene Expression Profiling, MicroRNAs, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Adaptor Proteins, Signal Transducing, GATA4 Transcription Factor, Mice, Interleukin-1alpha, Ataxia Telangiectasia Mutated Proteins
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