CoChat
Sign Up
Cited by 626TGF-β signaling in diseasesKruppel-like factors researchSignaling Pathways in Disease

TGF-β Family Signaling in the Control of Cell Proliferation and Survival

Open access
Zhang, Yun, Alexander, Peter B., Wang, Xiao-Fan·2017·Cold Spring Harbor Perspectives in Biology
DOI 10.1101/cshperspect.a022145PMC PMC5378054
Open this paper in CoChat — free accountOpen PDF

Abstract

The transforming growth factor β (TGF-β) family controls many fundamental aspects of cellular behavior. With advances in the molecular details of the TGF-β signaling cascade and its cross talk with other signaling pathways, we now have a more coherent understanding of the cytostatic program induced by TGF-β. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated by TGF-β and determine a cell's proliferation and survival, apoptosis, dormancy, autophagy, and senescence. The difficulty in defining TGF-β's roles partly stems from the context-dependent nature of TGF-β signaling. Here, we review our current understanding and recent progress on the biological effects of TGF-β at the cellular level, with the hope of providing a framework for understanding how cells respond to TGF-β signals in specific contexts, and why disruption of such mechanisms may result in different human diseases including cancer.

Integrity signals

Registry

Crossref · 10.1101/cshperspect.a022145

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 196 cited sources checked · 0 supported · 0 flagged

  • Interpretationcitation

    TGF-b can promote proliferation of some mesenchymal cell types, including kidney fibroblasts and smooth muscle cells.

    “However, this cytokine is able to promote proliferation of other mesenchymal cell types such as kidney fibroblasts and smooth muscle cells (Roberts et al. 1985;Battegay et al. 1990).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Roberts et al. 1985

      Not checked in the free run.

    • cites Battegay et al. 1990

      Not checked in the free run.

  • Interpretationcitation

    TGF-b plays a role in mediating cell dormancy.

    “several studies indicate that TGF-b plays a role in mediating cell dormancy (Salm et al. 2005;Yamazaki et al. 2011;Gao et al. 2012;Bragado et al. 2013)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Salm et al. 2005

      Not checked in the free run.

    • cites Yamazaki et al. 2011

      Not checked in the free run.

    • cites Gao et al. 2012

      Not checked in the free run.

  • Interpretationcitation

    TGF-b can either induce or suppress programmed cell death depending on the cell type.

    “TGF-b has been reported to either induce or suppress programmed cell death in different cell types (Schuster and Krieglstein 2002), although a consensus is still lacking in terms of a coherent mechanism for TGF-b to regulate apoptosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schuster and Krieglstein 2002

      Not checked in the free run.

  • Interpretationcitation

    Activated TGF-b receptor complexes can also signal through Smad-independent noncanonical pathways in certain cell types.

    “In addition, activated TGF-b receptor complexes can also function through Smad-independent, noncanonical pathways in certain cell types, adding another layer of complexity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Derynck and Zhang 2003

      Not checked in the free run.

  • Interpretationcitation

    Increased endoglin expression in endothelial cells shifts the TGF-b response from ALK-5 to ALK-1, promoting endothelial proliferation.

    “Increased expression of endoglin in endothelial cells shifts the TGF-b response from the ALK-5 pathway to the ALK-1 pathway, leading to the promotion of endothelial cell proliferation (Lebrin et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lebrin et al. 2004

      Not checked in the free run.

  • May combine two claims. 54
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Interpretationcitation

    TGF-b stimulation causes cytostasis in nearly all non-neoplastic epithelial cells and also in endothelial, hematopoietic, neuronal, and certain mesenchymal cells.

    “At the cellular level, TGF-b stimulation induces cytostasis in almost all non-neoplastic epithelial cells, as well as in endothelial cells, hematopoietic cells, neuronal cells and certain types of mesenchymal cells (Siegel and Massague ´2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Siegel and Massague ´2003

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Inhibitory Smads Smad6 and Smad7 compete with R-Smads for receptor association and reduce R-Smad phosphorylation and activation.

    “inhibitory Smads (Smad6 and Smad7) compete with R-Smads for association with the receptor complexes and thus decrease R-Smad phosphorylation and activation (Hayashi et al. 1997;Imamura et al. 1997;Nakao et al. 1997).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hayashi et al. 1997

      Not checked in the free run.

    • cites Imamura et al. 1997

      Not checked in the free run.

    • cites Nakao et al. 1997

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    MAPKs phosphorylate Smad1, Smad2, and Smad3 in their linker regions, impairing nuclear translocation and reducing TGF-b responses.

    “mitogen-activated protein kinases (MAPKs) are able to phosphorylate Smad1, Smad2, and Smad3 in their linker regions, leading to impaired nuclear translocation and reduced TGF-b responses (Kretzschmar et al. 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kretzschmar et al. 1997

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Formation of the ligand-receptor complex leads to phosphorylation and activation of type I receptors, enabling R-Smad binding.

    “Formation of this complex results in phosphorylation and activation of type I receptors, thereby allowing binding of receptor-regulated (R-) Smads.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Derynck and Zhang 2003

      Not checked in the free run.

    • cites Shi and Massague ´2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dab2 interacts with R-Smads and stabilizes receptor-Smad interactions.

    “Disabled-2 (Dab2) inter- acts with R-Smads and stabilizes the receptor-Smad interactions (Hocevar et al. 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hocevar et al. 2001

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial cells express ALK-1, which activates Smad1, 5, and 8, and ALK-5/TbRI, which activates Smad2 and 3.

    “Endothelial cells express two types of TGF-b type I receptors: ALK-1, which activates Smad1, 5, and 8, and ALK-5, also known as TbRI, which activates Smad2 and 3 (Oh et al. 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oh et al. 2000

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Accessory proteins at the cell membrane regulate TGF-b binding efficiency and specificity and can influence downstream responses.

    “The expression of accessory proteins at the cell membrane that regulate the binding efficiency and specificity of TGF-b for their receptors can also influence the downstream responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Betaglycan/TbRIII acts as a reservoir of TGF-b ligand and enhances cellular responsiveness when up-regulated by GIPC.

    “Betaglycan, also known as TbRIII, is another transmembrane protein that functions as a reservoir of the TGF-b ligand for TGF-b receptors, and enhances cellular responsiveness to TGF-b when up-regulated at the cell surface by the PDZ protein GIPC (Ga interacting protein (GAIP) interacting protein carboxyl terminus) (Blobe et al. 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Blobe et al. 2001

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Phosphorylation of betaglycan's cytoplasmic domain by TbRII triggers b-arrestin association and internalization of betaglycan and TbRII, suppressing TGF-b signaling.

    “the cytoplasmic domain of betaglycan can be phosphorylated by TbRII, triggering the association of b-arrestin with betaglycan and subsequent internalization of both betaglycan and TbRII, which in turn results in suppressed TGF-b signaling (Chen et al. 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al. 2003

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Activated ALK-1 increases endothelial proliferation and migration, while ALK-5 signaling suppresses these processes.

    “It has been shown that activated ALK-1 leads to increased proliferation and migration, whereas ALK-5 signaling suppresses these processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SARA regulates the subcellular localization of R-Smads and enhances their binding to receptors.

    “Smad anchor for receptor activation (SARA), regulates the subcellular localization of R-Smads and enhances their binding to receptors (Tsukazaki et al. 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tsukazaki et al. 1998

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    TGF-b signaling is required for vasculogenesis and angiogenesis during development and produces an angiogenic response in vivo.

    “TGF-b signaling is required for vasculogenesis and angiogenesis during development, and elicits an angiogenic response in vivo (Dickson et al. 1995;Larsson et al. 2001;Lebrin et al. 2005).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dickson et al. 1995

      Not checked in the free run.

    • cites Larsson et al. 2001

      Not checked in the free run.

    • cites Lebrin et al. 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The human genome contains seven type I TGF-b family receptors (ALK1-7) and five type II receptors (ActRIIA, ActRIIB, BMPRII, AMHRII, and TbRII).

    “The human genome encodes seven type I TGF-b family receptors (activin receptor-like kinases 1-7 [ALKs 1-7]) and five type II receptors (ActRIIA, ActRIIB, BMPRII, AMHRII, and TbRII).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Feng and Derynck 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Smad6 and Smad7 expression is induced by TGF-b as a feedback mechanism and by other signaling pathways as cross-talk nodes.

    “the expression of Smad6 and Smad7 is induced both by TGF-b signaling as a feedback mechanism and by other signaling pathways as nodes for signaling cross talk (Miyazono et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miyazono et al. 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    R-Smads are activated by phosphorylation at carboxy-terminal serines and released from receptor complexes.

    “Subsequently, R-Smads are activated through phosphorylation at carboxy-terminal serines and released from the receptor complexes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Derynck and Zhang 2003

      Not checked in the free run.

    • cites Shi and Massague ´2003

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Id1 inhibits E2A-dependent p21 expression and increases Rb phosphorylation by alleviating inhibition of CDK2.

    “Id1 inhibits E2A-dependent expression of p21 CIP1 and, in turn, increases the phosphorylation of Rb protein by alleviating the inhibition of CDK2 expression (Ruzinova and Benezra 2003;Perk et al. 2005;Lasorella et al. 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ruzinova and Benezra 2003

      Not checked in the free run.

    • cites Perk et al. 2005

      Not checked in the free run.

    • cites Lasorella et al. 2014

      Not checked in the free run.

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

    Premisenone given

    CDK2 must bind cyclin E to phosphorylate its substrates, whereas CDK4 or CDK6 needs to bind cyclin D.

    “To drive this progression, CDK2 must bind cyclin E to phosphorylate its substrates, whereas CDK4 or CDK6 needs to bind cyclin D.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    FoxO proteins associate with Smad3-Smad4 complexes in epithelial cells and induce p21 and p15, playing an important role in determining TGF-b cytostatic effects.

    “forkhead subfamily FoxO proteins have been shown to associate with Smad3-Smad4 complexes in epithelial cells and induce the expression of the CDK inhibitors p21 CIP1 and p15 INK4B , and thus play an important role in determining the cytostatic effects of TGF-b (Seoane et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Seoane et al. 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The ratio of Akt to Smad3 regulates cell sensitivity to TGF-b-mediated apoptosis, demonstrating PI3K-Akt pathway cross talk with the TGF-b pathway.

    “the ratio of Akt to Smad3 regulates the sensitivity of cells to TGF-b-mediated apoptosis, demonstrating a mechanism of phosphoinositide 3-kinase (PI3K)-Akt pathway cross talk with the TGF-b pathway (Conery et al. 2004;Remy et al. 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Conery et al. 2004

      Not checked in the free run.

    • cites Remy et al. 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    R-Smads engaged in transcription are rapidly phosphorylated in the linker region by CDK8 and CDK9, which facilitates cofactor recruitment but primes them for GSK3-mediated phosphorylation and degradation, terminating signaling.

    “R-Smads that are engaged in transcription become rapidly phosphorylated in the linker region by CDK8 and CDK9, two nuclear CDKs belonging to the transcriptional mediator and elongation complexes, respectively.This phosphorylation facilitates the recruitment of additional transcription cofactors but at the same time primes the linker region for GSK3-mediated phosphorylation and subsequent deg”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Alarcon et al. 2009

      Not checked in the free run.

    • cites Aragon et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    INK4 proteins including p15 specifically bind CDK4 and CDK6, inhibit their binding to cyclins, and inhibit cell-cycle progression.

    “INK4 (inhibitor of cyclin-dependent kinase 4) protein family proteins, which include p15 INK4B , specifically bind to CDK4 and CDK6 proteins, inhibit their binding to cyclins, and thus inhibit cell-cycle progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Activation of canonical Wnt signaling inactivates GSK3, increasing the stability of activated Smad1 and leading to cooperation between Wnt and TGF-b family pathways.

    “Activation of canonical Wnt signaling induces GSK3 inactivation, which augments the stability of activated Smad1, resulting in cooperation between Wnt and TGF-b family signaling pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    TGF-b suppresses expression of c-Myc and the differentiation inhibitors Id1, Id2, and Id3.

    “TGF-b suppresses the expression of several key transcription factors regulating growth control including the growth-promoting transcription factor c-Myc and cell differentiation inhibitors Id1, 2, and 3 (Fig. 2A) (Alexandrow and Moses 1995;Kang et al. 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Alexandrow and Moses 1995

      Not checked in the free run.

    • cites Kang et al. 2003

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    PKC and CaMKII phosphorylate Smad3 and Smad2, respectively, attenuating TGF-b signaling.

    “protein kinase C (PKC) and Ca 2þ /calmodulin-dependent kinase II (CaMKII) can also phosphorylate Smad3 and Smad2, respectively, leading to attenuated TGF-b signaling (Wicks et al. 2000;Yakymovych et al. 2001).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wicks et al. 2000

      Not checked in the free run.

    • cites Yakymovych et al. 2001

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Akt phosphorylates FoxO proteins, causing their translocation from the nucleus to the cytoplasm and preventing their association with Smads to induce p21.

    “Akt is able to phosphorylate FoxO proteins, resulting in FoxO translocation from the nucleus to the cytoplasm and effectively preventing their association with Smads to induce p21 CIP1 expression (Accili and Arden 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Accili and Arden 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Id proteins suppress cell differentiation and promote cell proliferation.

    “The Id proteins including Id1, Id2, and Id3, suppress the cell differentiation process and promote cell proliferation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    At the MYC promoter, a repressor complex containing Smad3, E2F4/5, DP1, and p107 is preassembled in the cytoplasm, translocates to the nucleus in response to TGF-b, binds DNA, and represses MYC transcription.

    “a repressor complex containing Smad3, E2F4/5, DP1, and corepressor p107, which is preassembled in the cytoplasm and translocated into the nucleus in response to TGF-b stimulation, can stably bind to DNA and thus repress MYC transcription (Chen et al. 2002;Yagi et al. 2002;Frederick et al. 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chen et al. 2002

      Not checked in the free run.

    • cites Yagi et al. 2002

      Not checked in the free run.

    • cites Frederick et al. 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Decreased c-Myc prevents cells from entering a growth-promoting state and primes CDK inhibitor gene promoters for activation by TGF-b.

    “the decrease of c-Myc expression not only directly prevents cells from entering a growth-promoting state (Eisenman 2001), but also primes the promoters of several important CDK inhibitor genes so they become responsive to further transcriptional activation in response to the same TGF-b signals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eisenman 2001

      Not checked in the free run.

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

    Premisenone given

    The G1-to-S transition requires activated CDKs including CDK2, CDK4, and CDK6.

    “It is known that the G 1 !S transition requires activated CDKs including CDK2, CDK4, and CDK6.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Akt phosphorylation enhances the Akt-Smad3 interaction in vivo, although it is not absolutely required for binding.

    “Although the phosphorylation of Akt is not absolutely necessary for Akt-Smad3 binding, it enhances this interaction in vivo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    CDK4 and CDK2 phosphorylate Smad3 in the linker region and suppress its transcriptional activity.

    “the G 1 cyclin-dependent kinases CDK4 and CDK2 also phosphorylate Smad3 in the linker region and suppress its transcriptional activity (Matsuura et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Matsuura et al. 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGF-b is a potent inducer of apoptosis in immature lymphocytes, maintaining immune homeostasis.

    “as well as for immature lymphocytes to maintain the homeostasis of the immune system (Li et al. 2006b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Li et al. 2006b

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    TGF-b's growth stimulatory effect on smooth muscle cells occurs only at low concentrations, whereas higher concentrations inhibit their proliferation.

    “TGF-b's growth stimulatory effect on smooth muscle cells only occurs at low concentrations, whereas higher concentrations of TGF-b inhibit their proliferation (Battegay et al. 1990).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Battegay et al. 1990

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    SKI and SKIL encode TGF-b antagonists that physically interact with R-Smads and disrupt their transcriptional complexes in carcinoma cells.

    “the well-characterized proto-oncogenes SKI and SKIL (encoding SnoN) encode TGF-b antagonists that physically interact with R-Smads and disrupt their transcriptional complexes in carcinoma cells (Deheuninck and Luo 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Deheuninck and Luo 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased SHIP results in decreased Akt phosphorylation and impaired cell survival.

    “Increased SHIP results in decreased Akt phosphorylation as well as impaired cell survival (Valderrama-Carvajal et al. 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Valderrama-Carvajal et al. 2002

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increased p15 disrupts existing p27-CDK4/6-cyclin-D complexes and leads to p27 redistribution.

    “partly because increased p15 INK4B disrupts the existing p27 KIP1 -CDK4/6-cyclin-D complexes and leads to p27 KIP1 redistribution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Most reports describe TGF-b as proapoptotic, though it can also suppress apoptosis.

    “Although TGF-b can either induce or suppress apoptosis, proapoptotic effects of TGF-b have been reported in most cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    At the distal CDKN1A promoter, Smad3/4 interacts with FoxO proteins, and the resulting Smad-FoxO complex induces p21.

    “At the distal region of the CDKN1A promoter that drives p21 CIP1 expression, the Smad3/4 complex interacts with FoxO subfamily proteins and the resulting Smad-FoxO complex can efficiently induce the expression of p21 CIP1 (Seoane et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Seoane et al. 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Active TGF-b maintaining HSC dormancy is mainly provided by nonmyelinating Schwann cells in bone marrow, making this glial cell type a novel component of HSC niche.

    “Surprisingly, the active form of TGF-b maintaining HSC dormancy is mainly provided by nonmyelinating Schwann cells, a type of glia that wraps around nerve fibers inside the bone marrow, making this glial cell type a novel component of the HSC niche (Yamazaki et al. 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yamazaki et al. 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During castration-induced involution, TGF-b signaling decreases at proximal region and primes stem cells to respond to mitogenic factors.

    “During castration-induced involution, TGF-b signaling decreases at the proximal region and thus primes the stem cells to respond to mitogenic factors (Salm et al. 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Salm et al. 2005

      Not checked in the free run.

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

    Premisecitation

    Programmed cellular senescence occurs naturally in certain tissues during normal embryonic development.

    “programmed cellular senescence seems to occur naturally in certain tissues during normal embryonic development (Mun ˜oz-Espı ´n et al. 2013;Storer et al. 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mun ˜oz-Espı ´n et al. 2013

      Not checked in the free run.

    • cites Storer et al. 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARTS is released from mitochondria upon TGF-b stimulation, leading to increased caspase 3 activity.

    “ARTS is released from mitochondria on TGF-b stimulation and this leads to increased caspase 3 activity (Larisch et al. 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Larisch et al. 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    For many stem cells and metastatic cancer cells, dormancy in a specific niche increases survival in stressful environments and promotes long-term repopulating activity.

    “For many stem cells and metastatic cancer cells, dormancy in a specific niche increases their ability to survive in stressful environments and promotes their long-term repopulating activity (Aguirre-Ghiso 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aguirre-Ghiso 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    4T1 cells express both mesenchymal and epithelial markers, and NMuMG cells undergo EMT in response to TGF-b.

    “However, it is interesting to note that 4T1 cells express both mesenchymal and epithelial markers and NMuMG cells undergo an EMT in response to TGF-b (Gal et al. 2008;Drasin et al. 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gal et al. 2008

      Not checked in the free run.

    • cites Drasin et al. 2011

      Not checked in the free run.

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

    Premisecitation

    Stress-induced senescence is thought to be important to pathogenesis of cancer and age-related tissue degeneration.

    “Whereas stress-induced senescence is thought to be important to the pathogenesis of cancer and age-related tissue degeneration (Campisi 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Campisi 2013

      Not checked in the free run.

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

    Premisecitation

    Autophagy is an evolutionarily conserved catabolic pathway that occurs in every cell at basal level to maintain cellular homeostasis.

    “This evolutionarily conserved pathway is thought to occur in every cell at a basal level to maintain cellular homeostasis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mizushima and Komatsu 2011

      Not checked in the free run.

    • cites Jiang and Mizushima 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Coco (Dante/Cerberuslike 2) is a secreted BMP antagonist that induces dormant breast cancer cells to reactivate in lung but not bone or brain, indicating organ-specific regulation of cancer cell dormancy.

    “Coco, also known as Dante or Cerberuslike 2, is a secreted antagonist of BMP ligands, and is reported to induce dormant breast cancer cells to reactivate in the lung, but not in the bone or brain, indicating an organ-specific regulation of cancer cell dormancy (Gao et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gao et al. 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGF-b induces Dec1 expression, a transcription factor known to suppress apoptosis, promoting cell survival in mouse mammary carcinoma cells.

    “TGF-b has also been reported to induce the expression of Dec1, a transcription factor known to suppress apoptosis, thus promoting cell survival in mouse mammary carcinoma cells (Ehata et al. 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ehata et al. 2007

      Not checked in the free run.

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

    Premisecitation

    Cellular senescence can be triggered by stresses including telomere shortening, DNA damage, and oncogene activation.

    “Senescence can be triggered by several known stresses including telomere shortening, DNA damage, and oncogene activation (Mun ˜oz-Espı ´n and Serrano 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mun ˜oz-Espı ´n and Serrano 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This proapoptotic effect is dysfunctional in Smad4 mutant pancreatic cancer cells because Snail induction requires the Smad4-containing transcriptional complex.

    “This proapoptosis effect of TGF-b is dysfunctional in Smad4 mutant pancreatic cancer cells because the induction of Snail requires the Smad4 containing transcriptional complex (David et al. 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites David et al. 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In lymphocytes and hepatocytes, Daxx directly interacts with TbRII, leading to JNK activation and enhanced apoptosis, similar to Fas-induced apoptosis.

    “In both lymphocytes and hepatocytes, Daxx is found to directly interact with TbRII, leading to the activation of JNK and enhanced apoptosis, in a similar manner to Fas-induced apoptosis (Perlman et al. 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Perlman et al. 2001

      Not checked in the free run.

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

    Premisecitation

    This secretion has been termed SASP and has pleiotropic effects on neighboring cells.

    “This has been termed the senescence-associated secretory phenotype (SASP), and has been shown to have pleiotropic effects on neighboring cells (Rodier and Campisi 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rodier and Campisi 2011

      Not checked in the free run.

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

    Premisenone given

    Senescent cells often express common markers including p15, p16, p21, p53, Rb, and SA-bgal.

    “Molecularly, senescent cells often express a common set of markers including the cell-cycle inhibitors p15 INK4B , p16 INK4A , and p21 CIP1 , the tumor suppressors p53 and Rb, and the lysosomal enzyme b-galactosidase (senescence-associated b-galactosidase, SA-bgal).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Daxx is an adaptor protein that binds Fas receptor, activates JNK pathway, and enhances Fas-mediated apoptosis.

    “Another example is the adaptor protein Daxx, which is known to bind the Fas receptor, activate the JNK pathway, and enhance Fas-mediated apoptosis (Yang et al. 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al. 1997

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGF-b rapidly stimulates cellular autophagy in hepatocellular carcinoma cells and mammary carcinoma cells, although precise mechanism is elusive.

    “TGFb has been shown to rapidly stimulate cellular autophagy in hepatocellular carcinoma cells and mammary carcinoma cells, although the precise mechanistic details underlying this phenotype are still elusive (Kiyono et al. 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kiyono et al. 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    hTERT transcription is under control of c-Myc, and in many human cancers TGF-b regulates hTERT indirectly by repressing c-Myc.

    “First, hTERT transcription is known to be under the control of the oncogene c-Myc, and in many human cancers TGF-b seems to regulate hTERTexpression indirectly by repressing c-Myc expression (Frederick et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Frederick et al. 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated TGF-b expression and Smad2 phosphorylation in mesonephros and endolymphatic sac of inner ear, and treatment of pregnant mice with TGF-b receptor antagonist led to diminished senescence in these locations in offspring.

    “Furthermore, elevated TGF-b expression and Smad2 phosphorylation in the mesonephros and endolymphatic sac of the inner ear, and treatment of pregnant mice with a TGF-b receptor antagonist led to diminished levels of senescence in these locations in the offspring of treated animals (Mun ˜oz-Espı ´n et al. 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mun ˜oz-Espı ´n et al. 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGF-b family ligands are not sufficient to induce prostate basal or mesenchymal stromal cell senescence, indicating cell-type-specific process.

    “Conversely, TGF-b family ligands are not sufficient to induce prostate basal (Untergasser et al. 2003) or mesenchymal stromal cell (Walenda et al. 2013) senescence, indicating that this process is cell-type-specific with additional molecules likely playing important roles.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Untergasser et al. 2003

      Not checked in the free run.

    • cites Walenda et al. 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Biological effects of TGF-b at cellular level, including inhibition or promotion of proliferation, apoptosis, dormancy, autophagy, and senescence, are basis for understanding physiological function in development and diseases.

    “The biological effects of TGF-b at the cellular level, including inhibition or promotion of proliferation, apoptosis, and cell dormancy and autophagy as well as cellular senescence, are the basis for understanding TGF-b's physiological function in development and diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BMP-7 induces breast and prostate cancer cell senescence, and in prostate p38 MAPK is involved.

    “BMP-7 has also been reported to induce breast and prostate cancer cell senescence (Cassar et al. 2009;Kobayashi et al. 2011), and in the latter case p38 MAPK also is involved.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cassar et al. 2009

      Not checked in the free run.

    • cites Kobayashi et al. 2011

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Compared with well-established TGF-b cytostatic program, mechanistic links between TGF-b and other processes are still too limited to generate a coherent picture.

    “Compared with the well-established TGF-b cytostatic program, the mechanistic links between TGFb and other processes are still too limited to generate a coherent picture.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    This limitation is partly because of context-dependent nature of TGF-b signaling, whose outcome differs dramatically in different cell types or cell states.

    “This is partly because of the context-dependent nature of TGF-b signaling, the outcome of which differs dramatically in different cell types or cell states.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Smad- and p53-mediated control of miRNA expression occurs at transcriptional and posttranscriptional levels; the latter uses a unique mechanism identified for Smad2/3 and p53.

    “Interestingly, Smad-and p53-mediated control of miRNA expression happens at both the transcriptional and posttranscriptional levels, the latter of which occurs using a unique molecular mechanism that has thus far only been identified for Smad2 and Smad3, and p53.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Suzuki et al. 2009

      Not checked in the free run.

    • cites Davis et al. 2010

      Not checked in the free run.

63 of 63

  • The paper relies on this without support.

    A cell's decision to divide depends largely on the balance of all signaling inputs from different growth factors and cytokines.

    “It should be noted that a cell's decision to divide largely relies on a balance of all the signaling inputs from different growth factors and cytokines.”
1 of 1

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?

  • In normal epithelial cells, TGF-β blocks G1 cell-cycle progression; this growth-suppressive pathway is viewed as incompatible with malignant transformation and cancer progression.

    “TGF-β inhibits cell proliferation in normal epithelial cells by inhibiting cell cycle progression through G1109-111, which is seen as a tumor suppressor pathway that is incompatible with malignant cell transformation and cancer progression111,112.”

    From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [110]

  • TGF-β promotes fibroblast proliferation.

    “Additionally, TGF-β promotes fibroblast proliferation110”

    From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [110]

  • TGF-β was initially found to potently inhibit proliferation of epithelial cells, and therefore seen as a tumor suppressor of carcinomas.

    “A primary reason for this delay was that TGF-β was initially found to potently inhibit proliferation of epithelial cells, and therefore seen as a tumor suppressor of carcinomas110,111,281–284.”

    From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [110]

Cites

Flagged first, then by citations

Research works printed but not linked: 155

  1. 10.1016/S0092-8674(04)00452-0 · DOI
  2. 10.1038/nrc2256 · DOI
  3. 10.1016/j.cell.2009.09.035 · DOI · Paper page
  4. 1995, Transforming growth factor β and cell cycle regulation, Cancer Res, 55, 1452
  5. 10.1101/gad.2060811 · DOI
  6. 10.1038/emboj.2009.291 · DOI
  7. 10.1016/0092-8674(90)90448-N · DOI
  8. 10.1073/pnas.2536483100 · DOI
  9. 2000, A mechanism of suppression of TGF-β/SMAD signaling by NF-κB/RelA, Genes Dev, 14, 187, 10.1101/gad.14.2.187 · DOI
  10. 10.1074/jbc.M106831200 · DOI
  11. 10.1158/0008-5472.CAN-08-1569 · DOI
  12. 2004, BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells, Am J Physiol Lung Cell Mol Physiol, 286, L81, 10.1152/ajplung.00160.2003 · DOI
  13. 10.1096/fj.08-119529 · DOI
  14. 2002, Dual regulation of telomerase activity through c-Myc-dependent inhibition and alternative splicing of hTERT, J Cell Sci, 115, 1305, 10.1242/jcs.115.6.1305 · DOI
  15. 10.1016/S0014-5793(99)01051-0 · DOI
  16. 10.1038/38008 · DOI
  17. 10.1073/pnas.98.3.992 · DOI
  18. 10.1016/S0092-8674(02)00801-2 · DOI
  19. 10.1126/science.1083195 · DOI
  20. 10.1128/MCB.25.18.8097-8107.2005 · DOI
  21. 10.1073/pnas.1015022108 · DOI · Paper page
  22. 10.1128/MCB.8.8.3088 · DOI
  23. 10.1038/ncb1117 · DOI
  24. 10.1073/pnas.92.12.5545 · DOI
  25. 10.1016/j.cell.2016.01.009 · DOI
  26. 10.1016/j.molcel.2010.07.011 · DOI
  27. 10.1242/jcs.01651 · DOI
  28. 10.1038/cr.2008.324 · DOI
  29. 10.1038/nature02006 · DOI
  30. 1995, Defective haematopoiesis and vasculogenesis in transforming growth factor-β 1 knock out mice, Development, 121, 1845, 10.1242/dev.121.6.1845 · DOI · Paper page
  31. 10.1074/jbc.M109.093724 · DOI
  32. 10.1007/s00441-011-1246-y · DOI · Paper page
  33. 10.1186/bcr3037 · DOI
  34. 10.1016/S0925-4773(02)00015-1 · DOI
  35. 10.1016/j.canlet.2004.06.008 · DOI
  36. 10.1074/jbc.C100008200 · DOI
  37. 10.1158/0008-5472.CAN-07-1522 · DOI
  38. 10.1101/gad928101 · DOI
  39. 2012, Crosstalk between p53 and TGF-β signalling, J Signal Transduct, 2012, 294097
  40. 10.1016/S0092-8674(00)80128-2 · DOI
  41. 10.1146/annurev.cellbio.21.022404.142018 · DOI · Paper page
  42. 10.1093/emboj/19.19.5178 · DOI
  43. 10.1128/MCB.24.6.2546-2559.2004 · DOI
  44. 10.1074/jbc.M006809200 · DOI
  45. 10.1016/j.cell.2007.09.027 · DOI
  46. 10.1038/sj.onc.1210741 · DOI
  47. 10.1016/j.molcel.2009.09.043 · DOI
  48. 10.1016/j.cell.2012.06.035 · DOI
  49. 10.1016/j.ccr.2006.07.019 · DOI
  50. 10.1093/emboj/21.7.1743 · DOI
  51. 10.1016/S0092-8674(00)80303-7 · DOI
  52. 10.1074/jbc.274.52.37461 · DOI
  53. 10.1093/emboj/20.11.2789 · DOI
  54. 10.1242/dev.01573 · DOI
  55. 10.1038/387417a0 · DOI
  56. 10.1038/39355 · DOI
  57. 10.1016/S0959-437X(03)00007-8 · DOI · Paper page
  58. 10.1038/ncb731 · DOI
  59. 10.1038/cr.2013.161 · DOI
  60. 10.1371/journal.pgen.1002359 · DOI
  61. 10.1016/S1097-2765(03)00109-6 · DOI
  62. 10.1006/bbrc.1999.0129 · DOI
  63. 10.1271/bbb.67.815 · DOI
  64. 10.1016/S1097-2765(00)00134-9 · DOI
  65. 10.1158/0008-5472.CAN-08-4401 · DOI
  66. 10.1084/jem.20110840 · DOI
  67. 10.2353/ajpath.2010.091012 · DOI
  68. 10.1038/39348 · DOI
  69. 10.1073/pnas.150152697 · DOI
  70. 10.1038/35046566 · DOI
  71. 10.1093/emboj/20.7.1663 · DOI · Paper page
  72. 10.1038/nrc3638 · DOI
  73. 10.1038/sj.emboj.7600386 · DOI
  74. 10.1016/j.cardiores.2004.10.036 · DOI
  75. 10.1038/sj.cr.7310023 · DOI
  76. 10.1146/annurev.immunol.24.021605.090737 · DOI
  77. 10.1016/j.cell.2006.03.044 · DOI
  78. 10.1091/mbc.E11-10-0849 · DOI
  79. 10.1016/j.molmed.2013.04.005 · DOI
  80. 10.1038/35043051 · DOI
  81. 10.1038/nrm3434 · DOI
  82. 10.1038/nature02650 · DOI
  83. 10.1053/j.gastro.2010.12.003 · DOI
  84. 10.1016/S0065-2776(00)75003-6 · DOI
  85. 10.1016/j.cell.2011.10.026 · DOI
  86. 10.1146/annurev.cellbio.13.1.261 · DOI
  87. 10.1038/nrm3823 · DOI · Paper page
  88. 10.1091/mbc.E02-07-0441 · DOI
  89. 10.1016/S0092-8674(03)01080-8 · DOI
  90. 10.1038/39369 · DOI
  91. 10.1038/35001602 · DOI
  92. 10.1073/pnas.97.6.2626 · DOI
  93. 10.1128/MCB.25.22.10017-10028.2005 · DOI
  94. 10.1074/jbc.M909467199 · DOI
  95. 10.4049/jimmunol.174.10.6169 · DOI
  96. 10.1038/nrc1673 · DOI
  97. 10.1038/35087019 · DOI
  98. 10.1101/gad.7.12a.2308 · DOI
  99. 10.1016/S0955-0674(97)80076-2 · DOI
  100. 10.1016/0092-8674(94)90572-X · DOI
  101. 10.1038/sj.onc.1209852 · DOI
  102. 2014, A dual role for autophagy in a murine model of lung cancer, Nat Commun, 5, 3056, 10.1038/ncomms4056 · DOI
  103. 10.1128/MCB.25.8.3338-3347.2005 · DOI
  104. 10.1038/ncb1113 · DOI
  105. 10.1101/gad.11.4.492 · DOI
  106. 10.1101/gad.9.15.1831 · DOI · Paper page
  107. 10.1074/jbc.274.49.35053 · DOI
  108. 10.1073/pnas.82.1.119 · DOI
  109. 10.1016/S0962-8924(03)00147-8 · DOI · Paper page
  110. 10.1083/jcb.200412015 · DOI
  111. 10.1074/jbc.M610172200 · DOI
  112. 10.1073/pnas.0406771101 · DOI
  113. 10.1002/1521-4141(200012)30:12<3680::AID-IMMU3680>3.0.CO;2-L · DOI
  114. 10.1007/s00441-001-0479-6 · DOI
  115. 10.1016/S0304-3940(02)00801-7 · DOI
  116. 10.1002/hep.23769 · DOI
  117. 10.1038/35070086 · DOI
  118. 10.1038/nature01119 · DOI
  119. 10.1016/S0092-8674(04)00298-3 · DOI
  120. 10.1016/S0092-8674(03)00432-X · DOI
  121. 10.1091/mbc.12.11.3328 · DOI
  122. 10.1126/science.1099993 · DOI
  123. 10.1038/359693a0 · DOI · Paper page
  124. 10.1038/nrc1208 · DOI
  125. 10.1074/jbc.M301413200 · DOI
  126. 10.1038/sj.emboj.7600917 · DOI
  127. 10.1038/35070076 · DOI
  128. 10.1016/j.cell.2013.10.041 · DOI · Paper page
  129. 10.1046/j.1523-1755.2001.059002579.x · DOI
  130. 10.1074/jbc.M807930200 · DOI
  131. 10.1042/BJ20100404 · DOI
  132. 10.1038/nature08199 · DOI
  133. 10.1172/JCI119418 · DOI
  134. 10.1016/0092-8674(87)90294-7 · DOI
  135. 10.1038/sj.onc.1203471 · DOI
  136. 10.1016/S0092-8674(00)81701-8 · DOI
  137. 10.1126/science.6093254 · DOI
  138. 1996, Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers, Cancer Res, 56, 5583
  139. 10.1038/17826 · DOI
  140. 10.1016/j.exger.2003.08.008 · DOI
  141. 10.1038/ncb885 · DOI
  142. 2003, Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model, Cancer Res, 63, 3447
  143. 10.1371/journal.pone.0077656 · DOI
  144. 10.1128/MCB.20.21.8103-8111.2000 · DOI
  145. 10.1158/0008-5472.CAN-05-1522 · DOI
  146. 10.1074/jbc.M104170200 · DOI
  147. 10.1096/fj.00-0474fje · DOI
  148. 10.1016/j.cell.2011.09.053 · DOI
  149. 10.1016/S0092-8674(00)80294-9 · DOI
  150. 2001, Autocrine transforming growth factor β suppresses telomerase activity and transcription of human telomerase reverse transcriptase in human cancer cells, Cell Growth Differ, 12, 119
  151. 10.1074/jbc.M307869200 · DOI
  152. 10.1038/sj.onc.1208262 · DOI
  153. 10.1038/sj.onc.1209634 · DOI · Paper page
  154. 10.1128/MCB.25.24.10731-10744.2005 · DOI
  155. 10.1074/jbc.M809393200 · DOI

Cited by

Sorted by citations

Authors
Zhang, Y., Alexander, P. B., & Wang, X.-F.
Affiliations
Duke Medical Center (US)
ORCID
Alexander, Peter B.
Venue
Cold Spring Harbor Perspectives in Biology
Publisher
Cold Spring Harbor Laboratory
Published
2016-12-05
Volume
9
Issue
4
Pages
a022145
ISSN
1943-0264 (ISSN-L)
DOI
10.1101/cshperspect.a022145
PMC
PMC5378054
OpenAlex
W2560689174
Semantic Scholar
f95b234dec7a33cb93a8911b11b5dba7cccf9ff6
Cited by
626
References
10
Citations by year
2026: 43 · 2025: 97 · 2024: 103 · 2023: 96 · 2022: 101 · 2021: 73 · 2020: 59 · 2019: 31 · 2018: 15 · 2017: 8
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA154586)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
TGF-beta signaling, cell proliferation, cell survival, apoptosis, cell cycle arrest, cell dormancy, autophagy, cellular senescence, context-dependent signaling, cancer
MeSH terms
Autophagy, Cell Survival, Humans, Signal Transduction, Transforming Growth Factor beta, Apoptosis, Cell Proliferation, Cell Cycle Checkpoints

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review