The DOI matches its Crossref record; 48 of the 49 references it cites were found in a registry or an index; 18 of the 68 sources its claims cite were checked for support.
STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration
Open accessAbstract
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.
Overview
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.
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Cites
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Verification
Claims the paper makes
18 of 68 cited sources checked · 8 supported · 1 flagged · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“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”
What the sources say
- Disputedcites [4] Li, 2001, Hepatology sourceExperimental — accuracy not yet measured
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.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Disputed
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration.”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
- Supportedcites [4] Li, 2001, Hepatology source
The Results report that Stat3 expression was induced twofold within two hours of partial hepatectomy. The introductory passage under Abstract reports reduced Stat3 induction in IL-6-deficient livers during regeneration, and the Discussion states that IL-6 activates Stat3 after hepatectomy. The paper also states that IL-6 is necessary for normal liver regeneration. Exact pages for these passages are not specified in our copy. (LLM, conf=0.92)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration.”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
- Supportedcites [4] Li, 2001, Hepatology source
The paper states that IL-6 is essential for normal liver regeneration (opening text following the Abstract). The Discussion also says its findings establish IL-6 as a critical component of the normal regenerative response. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
- Partly supportedcites [4] Li, 2001, Hepatology sourceExperimental — accuracy not yet measured
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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
- Supportedcites [4] Li, 2001, Hepatology source
The Abstract states that genes involved in G0/G1 transition and G1 progression showed reduced induction in IL-6−/− livers during regeneration. It also reports blunted DNA synthesis, liver necrosis and a risk of liver failure after partial hepatectomy, supporting the full citing sentence. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery source the paper cites for this claim was checked and supports it.
In the paper
“However, because IL-6 also activates other signaling pathways including the mitogen-activated protein kinase (MAPK) pathway during liver regeneration (4”
What the sources say
- Supportedcites [4] Li, 2001, Hepatology source
The Discussion states that MAPK activation is delayed in IL-6-deficient livers and that an IL-6 injection induces MAPK phosphorylation in the liver. It explicitly describes IL-6 activation of the MAPK pathway during liver regeneration as a mechanism complementary to Stat3 signaling. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Interleukin-6 (IL-6)1 is known as one of the most important initiators of the regenerative response (3”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
- Supportedcites [4] Li, 2001, Hepatology source
The Discussion describes IL-6 as an early stimulus during liver regeneration and a critical component of the normal regenerative response. It also links IL-6 to initiation of the regenerative process, supporting the paraphrase in the paper’s liver-regeneration context. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
- Supportedcites [4] Li, 2001, Hepatology source
The passage labeled Abstract states that IL-6-deficient mice have blunted DNA synthesis after 70% partial hepatectomy. This directly supports the attributed claim about a blunted DNA synthetic response during liver regeneration. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“their expression is likely to be directly regulated by STAT3 because their full transactivation requires the STAT binding elements in their promoters (19”
What the sources say
- Partly supportedcites [19] Wagner, 1990, EMBO J. sourceExperimental — accuracy not yet measured
The c-fos promoter experiments (section labeled Introduction; page unavailable) show that a SIF-binding element enhances c-sis/PDGF-induced transcription and that nonbinding mutations abolish induction in the tested constructs. The paper does not address junB or identify SIF as STAT3, and these experiments do not establish that STAT binding elements are required for full transactivation of both genes. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [27] Coffer, 1995, Oncogene
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In IL-6−/− livers, the first peak of MAPK activation is delayed until 12 h compared with 2 h posthepatectomy in IL-6+/+ livers”
What the sources say
- Supportedcites [4] Li, 2001, Hepatology source
The passage accompanying Fig. 6B (Hepatology, June 2001) reports peak p44/p42 MAPK phosphorylation at 2 hours posthepatectomy in IL-6+/+ livers, while activation in IL-6−/− livers was delayed until 12 hours. This matches the cited comparison. (LLM, conf=0.95)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
- Probably not a substantial claim. 14
- It may state two separate claims as one. 21
- The quote only partly states this claim. 1
Every source the paper cites for this claim was checked and supports it.
In the paper
“Specific disruption of STAT3 in T cells revealed that STAT3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis (13”
What the sources say
- Supportedcites [13] Takeda, 1998, J. Immunol. source
The paper’s summary (p. 4652) says the authors specifically disrupted Stat3 in T cells and found impaired IL-6-induced proliferation. The section on IL-6-induced Stat3 activation explains that IL-6 failed to prevent apoptosis in Stat3-deficient T cells, linking the proliferation effect to prevention of apoptosis. (LLM, conf=0.95)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A number of transformed cell lines as well as samples from human cancers are reported to contain constitutively activated STAT3.”
What the sources say
- Not checked — no full text of the sourcecites [20] Yu, 1995, Science source
- Partly supportedcites [21] Cao, 1996, Mol. Cell. Biol. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [22] Turkson, 2000, Oncogene source
- Not checked — no full text of the sourcecites [23] Danial, 1995, Science source
- Not checked — no full text of the sourcecites [24] Nielsen, 1997, Proc. Natl. Acad. Sci. U. S. A. source
- Partly supportedcites [25] Gouilleux-Gruart, 1996, Blood sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
What the sources say
- Not checked — no full text of the sourcecites [31] Schindler, 1995, Immunity source
- Not checked — no full text of the sourcecites [32] Schindler, 1995, Annu. Rev. Biochem. source
- Partly supportedcites [33] Seidel, 1995, Proc. Natl. Acad. Sci. U. S. A. sourceExperimental — accuracy not yet measured
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)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
What the sources say
- Not checked — no full text of the sourcecites [5] Leu, 2001, Mol. Cell. Biol. source
- Not checked — no full text of the sourcecites [38] Look, 1995, J. Biol. Chem. source
- Not checked — no full text of the sourcecites [39] Ohmori, 1997, J. Biol. Chem. source
- Partly supportedcites [40] Schaefer, 1995, Proc. Natl. Acad. Sci. U. S. A. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [41] Ichiba, 1998, J. Biol. Chem. source
- Partly supportedcites [42] Stocklin, 1996, Nature sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [43] Mikita, 1998, J. Immunol. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [44] Bhattacharya, 1996, Nature source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
- Partly supportedcites [18] Greenbaum, 1998, J. Clin. Invest. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [28] Cornell, 1990, Hepatology source
- Not matchedcites [29] Roselli, 1998, Am. J. Physiol.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [30] Yamada, 1997, Proc. Natl. Acad. Sci. U. S. A. source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Alb+STAT3fl/fl mice are fertile, they have no developmental abnormalities, and the gross morphology of the liver is also normal.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
In the paper
“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”
What the sources say
- Not checked — no full text of the sourcecites [17] Cressman, 1995, Hepatology source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“although mass restoration occurred as in IL-6−/− livers (3”
What the sources say
- Not checked — no full text of the sourcecites [3] Cressman, 1996, Science source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“whereas Alb+STAT3fl/fl animals were viable after hepatectomy with no signs of liver injury.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Because STAT3 deletion leads to embryonic lethality (12”
What the sources say
- Not checked — no full text of the sourcecites [12] Takeda, 1997, Proc. Natl. Acad. Sci. U. S. A. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Liver regeneration after a two-thirds partial hepatectomy provides an excellent in vivo model for studying cell cycle progression and cell proliferation (1”
What the sources say
- Not checked — no full text of the sourcecites [1] Michalopoulos, 1997, Science source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“From the knock-out mouse models now available, only STAT3 plays an essential role in early embryonic development (12”
What the sources say
- Not checked — no full text of the sourcecites [12] Takeda, 1997, Proc. Natl. Acad. Sci. U. S. A. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“There are two peaks of MAPK activation during regeneration, one at early G1 and the other during mid-late G1 phase.”
What the sources say
- Not checked — no full text of the sourcecites [47] Talarmin, 1999, Mol. Cell. Biol. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The upper band observed in the cyclin E blot (Fig. 7) was most likely the phosphorylated and inactive form of cyclin E.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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.”
What the sources say
- Not checked — no full text of the sourcecites [47] Talarmin, 1999, Mol. Cell. Biol. source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“the STAT-binding element in the JunB promoter does not bind or respond to STAT1 (27”
What the sources say
- Not checked — no full text of the sourcecites [27] Coffer, 1995, Oncogene
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The STAT1 knock-out has a specific defect in the interferon-γ response (46”
What the sources say
- Not checked — no full text of the sourcecites [46] Meraz, 1996, Cell source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the tissue-specific distribution of some STATs may also contribute to their functional specificity (45”
What the sources say
- Not checked — no full text of the sourcecites [45] Zhong, 1994, Proc. Natl. Acad. Sci. U. S. A. source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Furthermore, a constitutively active form of STAT3 causes cellular transformation in immobilized fibroblasts (26”
What the sources say
- Not checked — no full text of the sourcecites [26] Bromberg, 1999, Cell source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
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?
The cited source doesn’t support the claim as written.
In the citing paper
“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]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
Citations
Cites
Darnell, J. E., Kerr, L. M., & Stark, G. R. (1994) · Science · doi:10.1126/science.8197455 · Cited by 6,080
Experimental pathology of the liver
Higgins, G. (1931) · Medical Entomology and Zoology · Cited by 4,057
Darnell, J. E. (1997) · Science · doi:10.1126/science.277.5332.1630 · Cited by 3,979
Michalopoulos, G. K., & DeFrances, M. C. (1997) · Science · doi:10.1126/science.276.5309.60 · Cited by 2,828
Bromberg, J. F., Wrzeszczynska, M. H., Devgan, G., Zhao, Y., Pestell, R. G., Albanese, C., & Darnell, J. E. (1999) · Cell · doi:10.1016/s0092-8674(00)81959-5 · Cited by 2,790
Zhong, Z., Wen, Z., & Darnell, J. E. (1994) · Science · doi:10.1126/science.8140422 · Cited by 2,070
TRANSCRIPTIONAL RESPONSES TO POLYPEPTIDE LIGANDS: The JAK-STAT Pathway
Schindler, C., & Darnell, J. E. (1995) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.64.070195.003201 · Cited by 1,808
Meraz, M. A., White, J. M., Sheehan, K. C. F., Bach, E. A., Rodig, S. J., Dighe, A. S., Kaplan, D. H., Riley, J. K., Greenlund, A. C., Campbell, D., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81288-x · Cited by 1,656
Essential role of Stat6 in IL-4 signalling
Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S.-I., Nakanishi, K., Yoshida, N., Kishimoto, T., & Akira, S. (1996) · Nature · doi:10.1038/380627a0 · Cited by 1,557
Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice
Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furth, E. E., Poli, V., & Taub, R. (1996) · Science · doi:10.1126/science.274.5291.1379 · Cited by 1,538
Self-citation
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
- Higgins, 1931, Arch. Pathol., 12, 186
- Mohn, 1991, Mol. Cell. Biol., 11, 1393
- Coffer, 1995, Oncogene, 10, 985
- Roselli, 1998, Am. J. Physiol., 275, G1472
Cited by
Sorted by citations
Items 301–306 of 306
Cao, Z., Qin, L., Liu, K., Yao, C., Li, E., Hao, X., Wang, Μ., Jiang, B., Zou, Y., Hu, H., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.28.610033
“Mice with liver-specific knockout of Stat3 displayed fewer proliferating hepatocytes and delayed regeneration 26, 38 .”
BackgroundWei, W., & Schnabl, B. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.01.016
“…how b -hydroxybutyric acid mediates it’s effect in the liver, the authors hypothesized that transcription activator factor 3 (STAT3) might serve as a potential receptor for b -hydroxybutyric acid, given its implicated role in liver regeneration and its function as an epigenetic modifier 9,10 .”
Human hepatic cell line 5: In-vitro model for hepatic immunobiology
Shrestha, S., Yeong, M. Y., Cheng, X. Y., Wang, W. J., Bhayana, N., Verma, N. K., Bao, Y., & Wang, Y. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-11502-w
“Protein markers for proliferation, cytochrome enzymes, and oxidation are essential for evaluating hepatocyte cell line suitability as models for liver function and disease research [45, 46].”
Biological Roles of the STAT Family in Cytokine Signaling
Takeda, K., & Akira, S. (2004) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-18932-6_4
Metadata
- 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
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 32
- Pages
- 28411-28417
- ISSN
- 0021-9258 (ISSN-L)
- 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
- hybrid
- doi.org
- 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
- Life Sciences › Immunology and Microbiology › Immunology › 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.
A language model drew the claims from the paper on 2026-10-23, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-23 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (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.
What counts as a claim ›How we measure confidence ›How we check this ›
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