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Cited by 307Liver physiology and pathologyCytokine Signaling Pathways and InteractionsOrgan Transplantation Techniques and Outcomes

STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration

Open access
Li, Wei, Liang, Xianping, Kellendonk, Christoph, Poli, Valeria, Taub, Rebecca·2002·Journal of Biological Chemistry
DOI 10.1074/jbc.m202807200
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Abstract

STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration. We wanted to know whether STAT3 was also required for liver regeneration but disruption of the STAT3 gene during embryonic stages causes lethality. Therefore, an albumin promoter-driven Cre-loxP recombination system was used to create a STAT3 deletion in the adult mouse liver to study the role of STAT3 in liver regeneration. After partial hepatectomy, there was virtually no STAT3 RNA or protein induction in Alb(+) STAT3(fl/fl) livers. STAT3 DNA binding activity was also absent in Alb(+) STAT3(fl/fl) livers. Unlike in control livers, STAT1 was activated in STAT3 conditional-mutant livers posthepatectomy. Hepatocyte DNA synthesis at 40 h posthepatectomy in Alb(+) STAT3(fl/fl) livers was reduced to approximately one-third of the control. Alb(+) STAT3(fl/fl) livers had abnormalities in immediate-early gene activation that largely correlated with but were not identical to those seen in IL-6-/- livers. G(1) phase cyclins including cyclins D1 and E had lower expression levels in Alb(+) STAT3(fl/fl) livers, indicating an abnormal G(1) to S phase transition. Therefore, STAT3 accounts for part of the DNA synthetic response of the hepatocytes during liver regeneration, which cannot be compensated for by induction of STAT1. Normal activation of the MAPK pathway in Alb(+) STAT3(fl/fl) livers reinforces the fact that at least part of the effect of IL-6 on hepatocyte proliferation is not mediated by STAT3. This study provides the first in vivo evidence that STAT3 promotes cell cycle progression and cell proliferation under physiological growth conditions.

AI snapshot

Written from the paper’s full text.

TL;DR

Using an albumin promoter–driven Cre-loxP system to delete STAT3 in adult mouse liver, this study shows that STAT3 is required for part of the hepatocyte DNA synthetic response after partial hepatectomy. It provides the first in vivo evidence that STAT3 promotes cell cycle progression under physiological growth conditions.

Key findings

  • STAT3 deletion was efficient: more than 90% deletion of the STAT3 gene, with virtually no STAT3 mRNA, nuclear protein, or DNA binding activity in Alb+STAT3fl/fl livers after partial hepatectomy.
  • Hepatocyte DNA synthesis at 40 h posthepatectomy in Alb+STAT3fl/fl livers was reduced to approximately one-third of control (a 3-fold difference, p < 0.02), with reduced DNA synthesis at other time points; liver mass was nonetheless regained normally after 1 week with no sign of injury.
  • In the absence of STAT3, STAT1 was activated instead: a high level of a complex migrating at the STAT1 homodimer position appeared posthepatectomy, confirmed by supershift with anti-STAT1 but not anti-STAT3 antibody, and nuclear STAT1 protein was markedly induced.
  • Immediate-early gene activation was abnormal but not identical to IL-6−/− livers: c-fos and junB were significantly reduced at all time points, c-myc peak activation was delayed, IGFBP-1 was reduced 2-fold at 2 h (vs. more than 3-fold in IL-6−/−), and Egr-1 was up-regulated rather than down-regulated. Of 10 STAT3 target genes, only 1 (lymphotoxin receptor) had not previously been identified as an IL-6 target.
  • G1 phase cyclins were partially impaired: cyclin D1 was normal early but reduced at the peak of DNA synthesis (40 h) and remained low; cyclin E induction was delayed until 32 h (vs. 16 h in controls) and lower at later time points.
  • MAPK activation followed the same kinetics as controls with no consistent or significant difference in phosphorylated Erk1 or Erk2 at any time point, supporting STAT3 and MAPK as independent IL-6 signaling pathways.

Methods

  • Liver-specific STAT3 conditional knockout: STAT3fl/fl mice crossed to albumin promoter–driven Cre transgenic mice to generate Alb+STAT3fl/fl mice and Alb−STAT3fl/fl littermate controls; F1 progeny used in all experiments.
  • 8–12-week-old mice underwent two-thirds partial hepatectomy (left lateral and median lobes removed) and were sacrificed at various time points; BrdUrd immunohistochemistry quantified labeled hepatocyte nuclei in 12 random 20× fields (~200 cells/field).
  • Analyses included Northern blot, Western blot of whole and nuclear liver extracts, electrophoretic mobility shift assay with supershift, cDNA microarray of RNA at 2 h posthepatectomy, and serum index testing.

Limitations

  • Stated by the paper: whether STAT1 can substitute for STAT3 in binding HNF-1 requires further analysis; it is unknown whether cyclin E is regulated by IL-6 during liver regeneration because cyclin E expression was not examined in IL-6−/− livers; other IL-6-activated signaling pathways important for normal liver cell function during regrowth await characterization.
  • Evident from the text: the microarray comparison was performed at a single time point (2 h posthepatectomy), and the mechanism by which STAT3 normally inhibits STAT1 activation is described as unknown.

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

Integrity signals

Registry

Crossref · 10.1074/jbc.m202807200

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

18 of 68 cited sources checked · 8 supported · 1 flagged · accuracy not yet measured

  • Findingcitation
    § RESULTS

    Three IL-6 target genes did not show IL-6 regulation posthepatectomy but were activated by IL-6 injection in the liver (TDAG51, membrane glycoprotein gp130, and Erp72).

    “Three did not show IL-6 regulation posthepatectomy but were activated by IL-6 injection in the liver (TDAG51, membrane glycoproteingp130, and Erp72, the endoplasmic reticulum stress protein) (4”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Li, 2001, Hepatology source

      Table 1 (HEPATOLOGY June 2001 section; page not supplied) lists ERp72, gp130, and TDAG51 with differential expression between IL-6-positive and IL-6-deficient livers two hours after hepatectomy. That is contrary to the claim that these three showed no IL-6 regulation posthepatectomy. The table passage does not clearly establish the claimed injection result for all three. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation
    § Abstract

    STAT3 is rapidly induced during liver regeneration in an IL-6-dependent fashion.

    “STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Cressman, 1996, Science source
    • cites [4] Li, 2001, Hepatology source
  • Premisecitation
    § Abstract

    IL-6 is required for normal liver regeneration.

    “STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Cressman, 1996, Science source
    • cites [4] Li, 2001, Hepatology source
  • Premisecitation
    § Abstract

    IL-6−/− mice have impaired liver regeneration characterized by liver necrosis and failure.

    “IL-6−/− mice have impaired liver regeneration characterized by liver necrosis and failure, a blunted DNA synthetic response in hepatocytes, and reduced gene activation during G1 phase.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Cressman, 1996, Science source
    • cites [4] Li, 2001, Hepatology source

      The introductory passage following the Abstract says IL-6-deficient mice have impaired regeneration and liver necrosis after 70% partial hepatectomy. It says they are prone to liver failure, rather than stating that liver failure occurs in all such mice; the claim omits that qualification. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Abstract

    IL-6−/− mice have reduced gene activation during G1 phase.

    “IL-6−/− mice have impaired liver regeneration characterized by liver necrosis and failure, a blunted DNA synthetic response in hepatocytes, and reduced gene activation during G1 phase.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Cressman, 1996, Science source
    • cites [4] Li, 2001, Hepatology source
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 21
  • The quote only partly states this claim. 1

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

    Premisecitation
    § Abstract

    Specific disruption of STAT3 in T cells revealed that STAT3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis.

    “Specific disruption of STAT3 in T cells revealed that STAT3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis (13”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Takeda, 1998, J. Immunol. source

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

    Premisecitation
    § DISCUSSION

    A number of transformed cell lines as well as samples from human cancers are reported to contain constitutively activated STAT3.

    “A number of transformed cell lines as well as samples from human cancers are reported to contain constitutively activated STAT3.”
    Quote in the paperNot a substantial claim2 of 6 sources checked
    • cites [20] Yu, 1995, Science source
    • cites [21] Cao, 1996, Mol. Cell. Biol. source

      The Abstract (p. 1595) reports constitutively activated Stat3 in all v-Src-transformed cell lines examined. Our copy does not report the same finding in samples from human cancers, so that part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [22] Turkson, 2000, Oncogene source
    • cites [23] Danial, 1995, Science source
    • cites [24] Nielsen, 1997, Proc. Natl. Acad. Sci. U. S. A. source
    • cites [25] Gouilleux-Gruart, 1996, Blood source

      The Results report constitutive DNA-binding by a STAT3-related factor in several patients’ AML samples, supporting the human-cancer-sample part of the claim. The Discussion also cites STAT3-related activity in Src-transformed cells, but it does not establish constitutively activated STAT3 in a number of transformed cell lines; it notes that the factor detected in AML may differ from STAT3. The indexed passages provide no page numbers. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § DISCUSSION

    The STAT family consists of seven members that in vitro bind a similar consensus DNA element, TTCnnn(n)GAA.

    “The STAT family consists of seven family members, and in vitro they bind to a similar consensus element on the DNA, TTCnnn(n)GAA (31-33”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [31] Schindler, 1995, Immunity source
    • cites [32] Schindler, 1995, Annu. Rev. Biochem. source
    • cites [33] Seidel, 1995, Proc. Natl. Acad. Sci. U. S. A. source

      The indexed passage on STAT-binding elements (Abstract, p. 3041) supports binding to a broadly similar palindromic DNA element, describing a general TT(N)5AA structure and testing different half-site spacings. It does not state that the STAT family has seven members, or establish the exact TTCnnn(n)GAA consensus given in the claim. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Abstract

    Although STATs bind a similar DNA binding site, they may interact with co-activators or co-repressors to regulate different sets of their own downstream targets.

    “Although they bind to a similar DNA binding site, STATs may interact with co-activator or co-repressor to regulate different sets of their own downstream targets (5”
    Quote in the paperNot a substantial claim3 of 8 sources checked
    • cites [5] Leu, 2001, Mol. Cell. Biol. source
    • cites [38] Look, 1995, J. Biol. Chem. source
    • cites [39] Ohmori, 1997, J. Biol. Chem. source
    • cites [40] Schaefer, 1995, Proc. Natl. Acad. Sci. U. S. A. source

      The Discussion (page not provided) reports cooperative activation of a promoter by Stat3β and c-Jun and suggests this could matter for responses involving other STAT proteins. It does not establish that STATs generally bind similar DNA sites or interact with co-repressors to regulate different sets of downstream targets. The similar-site discussion in the introduction concerns Jun and Fos proteins, not STATs. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [41] Ichiba, 1998, J. Biol. Chem. source
    • cites [42] Stocklin, 1996, Nature source

      The paper reports that the glucocorticoid receptor acts as a co-activator for Stat5 and proposes that different co-activators could contribute to signaling specificity. It does not establish that STAT family members bind similar DNA sites or interact with co-repressors to regulate distinct sets of downstream targets (section “Functional interactions between Stat5 and the glucocorticoid receptor”; page unavailable in our copy). (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [43] Mikita, 1998, J. Immunol. source

      The Discussion (page unavailable) says STAT proteins can cooperate with other transcription factors and that the interactions probably depend on promoter context; it demonstrates Stat6–C/EBPβ synergy at one promoter. It does not establish that different STATs bind similar DNA sites or that co-repressors help them regulate distinct sets of downstream targets. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [44] Bhattacharya, 1996, Nature source

  • May combine two claims.

    Premisecitation
    § DISCUSSION

    Regaining liver mass despite deficient DNA synthesis is a general phenomenon in animal models defective in liver regeneration, most likely resulting from hypertrophy of hepatocytes despite G1/S arrest.

    “Regaining liver mass despite deficient DNA synthesis is a general phenomenon in animal models that are defective in liver regeneration, which most likely results from hypertrophy of hepatocytes despite G1/S arrest (3”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [3] Cressman, 1996, Science source
    • cites [18] Greenbaum, 1998, J. Clin. Invest. source

      The Results report markedly reduced DNA synthesis in C/EBPβ-deficient mice without a statistically significant difference in liver-mass reconstitution. The Discussion proposes increased cell size during G1 as an explanation and suggests that the cell-cycle block may occur near G1/S. It does not establish this as a general phenomenon across animal models or demonstrate hepatocyte hypertrophy despite a confirmed G1/S arrest. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [28] Cornell, 1990, Hepatology source
    • cites [29] Roselli, 1998, Am. J. Physiol.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [30] Yamada, 1997, Proc. Natl. Acad. Sci. U. S. A. source

  • May combine two claims.

    Findingown data
    § RESULTS

    In Alb+STAT3fl/fl livers after surgery, there is little STAT3/STAT3 homodimer but a high level of complex migrating at the position of the STAT1 homodimer.

    “In contrast, there was little STAT3/STAT3 homodimer observed in Alb+STAT3fl/fl livers after surgery, but a high level of complex was detected migrating at the position of the STAT1 homodimer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    More than 100 immediate-early genes are activated at 2 h posthepatectomy, 36% of which also showed IL-6 regulation posthepatectomy.

    “By using a mouse cDNA expression array, we successfully identified more than 100 immediate-early genes that are activated at 2 h posthepatectomy, 36% of which also showed IL-6 regulation posthepatectomy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    There was a 3-fold difference in the number of hepatocytes undergoing DNA synthesis at 40 h posthepatectomy (p < 0.02) and reduced DNA synthesis at other time points.

    “There was a 3-fold difference in the number of hepatocytes undergoing DNA synthesis at 40 h posthepatectomy (p < 0.02) and reduced DNA synthesis at other time points (Fig. 3, A andB)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    STAT3 protein is not present in the nucleus in quiescent livers, but its level rises rapidly and peaks around 2 h posthepatectomy in Alb−STAT3fl/fl livers.

    “STAT3 was not present in the nucleus in quiescent livers, but the level went up rapidly and peaked around 2 h posthepatectomy in Alb−STAT3fl/fl livers (Fig. 1 B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Alb+STAT3fl/fl animals regained liver mass normally after 1 week of surgery showing no sign of injury at any time point posthepatectomy.

    “Alb+STAT3fl/fl animals regained liver mass normally after 1 week of surgery showing no sign of injury at any time point posthepatectomy (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    In control livers, STAT3 mRNA is rapidly induced after surgery and remains high until 24 h posthepatectomy, whereas there is only minimum induction in Alb+STAT3fl/fl livers.

    “In control livers, the message was rapidly induced after surgery and remained high until 24 h posthepatectomy, whereas there was only minimum induction of the STAT3 mRNA in Alb+STAT3fl/fl livers (Fig.1 A).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § RESULTS

    Alb+STAT3fl/fl mice are viable and fertile, have no developmental abnormalities, and the gross morphology of the liver is normal.

    “Alb+STAT3fl/fl mice are fertile, they have no developmental abnormalities, and the gross morphology of the liver is also normal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § RESULTS

    A low level of STAT3/STAT1 heterodimer and an even lower level of STAT1 homodimer are observed in control livers.

    “A low level of STAT3/STAT1 heterodimer as well as an even lower level of STAT1 homodimer band were also observed as we have reported previously (17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Cressman, 1995, Hepatology source

  • May combine two claims.

    Findingown data
    § RESULTS

    In Alb+STAT3fl/fl livers, the putative STAT1/STAT1 homodimer was disrupted by α-STAT1 antibody, and α-STAT3 antibody had no effect.

    “but the putative STAT1/STAT1 homodimer in Alb+STAT3fl/fl livers was disrupted by the α-STAT1 antibody. α-STAT3 antibody had no effect on this complex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    In control livers, the main DNA binding band was supershifted by α-STAT3 antibody, and anti-STAT1 antibody had no effect.

    “When preincubated with α-STAT3 antibody, the main DNA binding band in Alb− STAT3fl/fllivers was supershifted, and multiple supershift complexes were formed. Anti-STAT1 antibody had no effect on this complex”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § DISCUSSION

    Liver mass restoration occurred in the absence of STAT3 as it does in IL-6−/− livers.

    “although mass restoration occurred as in IL-6−/− livers (3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Cressman, 1996, Science source

  • May combine two claims.

    Findingown data
    § RESULTS

    Cyclin D1 expression is normal at earlier time points during the cell cycle but is reduced at the peak of DNA synthesis (40 h posthepatectomy) and remains low at all later time points in Alb+ compared with Alb−STAT3fl/fl livers.

    “Cyclin D1 expression was normal at earlier time points during the cell cycle but was reduced at the peak of DNA synthesis (40 h posthepatectomy) and remained low at all later time points in the Alb+ compared with Alb−STAT3fl/fl livers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    IGFBP-1 expression level is 2-fold lower in Alb+STAT3fl/fl livers than control livers, compared with more than 3-fold lower in IL-6−/− livers.

    “Its expression level is 2-fold lower in Alb+ STAT3fl/fl livers than control livers compared with more than 3-fold lower in IL-6−/− livers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Egr-1 is expressed at a lower level at 2 h posthepatectomy in IL-6−/− livers but at a higher level at all time points in Alb+STAT3fl/fl livers compared with Alb−STAT3fl/fl livers.

    “Interestingly, Egr-1 is expressed at a lower level at 2 h posthepatectomy in IL-6−/− livers but a higher level at all time points in Alb+STAT3fl/fl livers compared with Alb− STAT3fl/fl livers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    The STAT1 protein level is markedly induced in the nucleus of Alb+STAT3fl/fl livers posthepatectomy, whereas control livers show only a slight increase.

    “The STAT1 protein level was markedly induced in the nucleus of Alb+STAT3fl/fl livers, whereas in control livers there was only a slight increase in the STAT1 level posthepatectomy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given
    § Abstract

    Alb+STAT3fl/fl animals were viable after hepatectomy with no signs of liver injury.

    “whereas Alb+STAT3fl/fl animals were viable after hepatectomy with no signs of liver injury.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Abstract

    Disruption of the STAT3 gene during embryonic stages causes lethality.

    “Because STAT3 deletion leads to embryonic lethality (12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Takeda, 1997, Proc. Natl. Acad. Sci. U. S. A. source

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Liver regeneration after a two-thirds partial hepatectomy provides an excellent in vivo model for studying cell cycle progression and cell proliferation.

    “Liver regeneration after a two-thirds partial hepatectomy provides an excellent in vivo model for studying cell cycle progression and cell proliferation (1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Michalopoulos, 1997, Science source

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

    Premisecitation
    § Abstract

    STAT3 belongs to the family of STAT transcription factors which mediate the cellular response to a variety of cytokines and growth factors including IL-6.

    “Signal transducer and activator of transcription 3 (STAT3) belongs to the family of STAT transcription factors which mediate the cellular response to a variety of cytokines and growth factors including IL-6 (6-8”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Darnell, 1994, Science source
    • cites [7] Darnell, 1997, Science source
    • cites [8] Ihle, 1996, Cell source

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

    Premisecitation
    § Abstract

    Among the knock-out mouse models now available, only STAT3 plays an essential role in early embryonic development.

    “From the knock-out mouse models now available, only STAT3 plays an essential role in early embryonic development (12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Takeda, 1997, Proc. Natl. Acad. Sci. U. S. A. source

  • May combine two claims.

    Premisecitation
    § Abstract

    There are two peaks of MAPK activation during regeneration, one at early G1 and the other during mid-late G1 phase.

    “There are two peaks of MAPK activation during regeneration, one at early G1 and the other during mid-late G1 phase.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Talarmin, 1999, Mol. Cell. Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § RESULTS

    The upper band observed in the cyclin E blot is most likely the phosphorylated and inactive form of cyclin E.

    “The upper band observed in the cyclin E blot (Fig. 7) was most likely the phosphorylated and inactive form of cyclin E.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Abstract

    In rat liver the second peak of MAPK activation occurs around 10.5 h, whereas in mouse liver it is around 24 h posthepatectomy, corresponding to a later S phase onset in the mouse liver.

    “In rat liver, the second peak of activation occurs around 10.5 h, whereas in mouse liver it is around 24 h posthepatectomy, corresponding to a later S phase onset in the mouse liver.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Talarmin, 1999, Mol. Cell. Biol. source

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

    Premisecitation
    § Abstract

    The STAT-binding element in the JunB promoter does not bind or respond to STAT1.

    “the STAT-binding element in the JunB promoter does not bind or respond to STAT1 (27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Coffer, 1995, Oncogene

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

    Premisecitation
    § Abstract

    The STAT1 knock-out has a specific defect in the interferon-γ response.

    “The STAT1 knock-out has a specific defect in the interferon-γ response (46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Meraz, 1996, Cell source

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

    Premisecitation
    § Abstract

    The tissue-specific distribution of some STATs may contribute to their functional specificity.

    “the tissue-specific distribution of some STATs may also contribute to their functional specificity (45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Zhong, 1994, Proc. Natl. Acad. Sci. U. S. A. source

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

    Premisecitation
    § DISCUSSION

    A constitutively active form of STAT3 causes cellular transformation in immobilized fibroblasts.

    “Furthermore, a constitutively active form of STAT3 causes cellular transformation in immobilized fibroblasts (26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Bromberg, 1999, Cell source
32 of 32

  • The paper relies on this without support.

    The STAT3 conditional deletion in the liver is specific to hepatocytes and does not affect other liver cell types.

    “The albumin promoter was chosen to drive the Cre recombinase to obtain liver-specific deletion of the STAT3 gene.”

  • The paper relies on this without support.

    The STAT1 DNA binding activity observed in Alb+STAT3fl/fl livers represents functional STAT1 signaling capable of compensating for STAT3 loss.

    “Unlike in control livers, STAT1 was activated in STAT3 conditional-mutant livers posthepatectomy.”

  • The paper relies on this without support.

    The immediate-early gene expression changes at 2 h posthepatectomy are causally responsible for the subsequent hepatocyte DNA synthesis at 40 h.

    “This is the first in vivo evidence that STAT3 promotes cell cycle progression and cell proliferation by up-regulating immediate-early growth response genes.”
3 of 3

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?

  • Successful liver regeneration depends on an intact TNF-NFκB-IL-6-STAT3 pathway.

    “Successful LR depends on an intact TNF-NFκB-IL-6-STAT3 pathway.”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [27]

    The Abstract reports that hepatocyte DNA synthesis was impaired without STAT3, but liver regeneration still occurred. The Discussion likewise says liver mass was restored despite deficient DNA synthesis. These findings contradict the claim that successful regeneration depends on an intact pathway through STAT3. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • IL-6 is the central trigger of liver regeneration via phosphorylation/activation of STAT3.

    “IL-6, produced following hepatectomy by Kupffer cells and hepatocytes (25), is the central trigger of LR via phosphorylation/activation of STAT3 (27).”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [27]

    The Abstract calls IL-6 one of the most important initiators of liver regeneration and says STAT3 is induced in an IL-6-dependent fashion. It also reports that regeneration still occurred without STAT3 and that some IL-6 effects are mediated by other pathways. The paper supports IL-6–STAT3 signaling as an important contributor, but not the stronger claim that it is the central trigger of regeneration via STAT3 alone. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The effect of liver-specific Stat3 deletion on liver regeneration was relatively modest.

    “By contrast, the effect of liver-specific Stat3 deletion was relatively modest (71, 72)”

    From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [71]

Cites

Flagged first, then by citations

1 of the 49 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. Higgins, 1931, Arch. Pathol., 12, 186
  2. Mohn, 1991, Mol. Cell. Biol., 11, 1393
  3. Coffer, 1995, Oncogene, 10, 985
  4. Roselli, 1998, Am. J. Physiol., 275, G1472

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Authors
Li, W., Liang, X., Kellendonk, C., Poli, V., & Taub, R.
Affiliations
  • University of Pennsylvania (US)
  • Columbia University (US)
  • University of Dundee (GB)
Corresponding author
Taub, Rebecca
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-08
Volume
277
Issue
32
Pages
28411-28417
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m202807200
OpenAlex
W2052467994
Cited by
307
References
49
Citations by year
2026: 1 · 2025: 7 · 2024: 4 · 2023: 11 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 15 · 2017: 10 · 2016: 9 · 2015: 17 · 2014: 13 · 2013: 11 · 2012: 23
FWCI
8.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders
  • National Institutes of Health (5r01dk058315-05, 5p30dk050306-29)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 58315, P30DK50306)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
STAT3, liver regeneration, hepatocyte proliferation, interleukin-6, STAT1, partial hepatectomy, G1/S transition, MAPK signaling, hepatocyte DNA synthesis
MeSH terms
Animals, Bromodeoxyuridine, Cell Division, DNA, DNA-Binding Proteins, Immunohistochemistry, Liver, Regeneration, Time Factors, Blotting, Northern, Blotting, Western, Signal Transduction, Trans-Activators, DNA, Complementary, Cyclin E, Cyclin D1, Oligonucleotide Array Sequence Analysis, MAP Kinase Signaling System, Hepatocytes, STAT1 Transcription Factor, STAT3 Transcription Factor, Mice

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 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

Cited sources are checked by gpt-6-sol.

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.

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