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.
Integrity signals
Registry
Cites
Statistics
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
Liver regeneration: from myth to mechanism
Taub, R. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1489 · Cited by 1,567
Self-citationMichalopoulos, G. K. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21172 · Cited by 1,384
Fausto, N., Campbell, J. S., & Riehle, K. J. (2006) · Hepatology · doi:10.1002/hep.20969 · Cited by 1,378
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome
Minegishi, Y., Saitō, M., Tsuchiya, S., Tsuge, I., Takada, H., Hara, T., Kawamura, N., Ariga, T., Pašić, S., Stojković, O., et al. (2007) · Nature · doi:10.1038/nature06096 · Cited by 1,075
Mechanisms of Acetaminophen-Induced Liver Necrosis
Hinson, J. A., Roberts, D. W., & James, L. P. (2010) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-00663-0_12 · Cited by 1,006
The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer
Naugler, W. E., & Karin, M. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.12.007 · Cited by 730
Signal Transducer and Activator of Transcription‐3, Inflammation, and Cancer
Aggarwal, B. B., Kunnumakkara, A. B., Harikumar, K. B., Gupta, S. R., Tharakan, S. T., Koca, C., Dey, S., & Sung, B. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04911.x · Cited by 663
Zenewicz, L. A., Yancopoulos, G. D., Valenzuela, D. M., Murphy, A. J., Karow, M. L., & Flavell, R. A. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.023 · Cited by 648
“Triggering both of these well-described pathways leads to activation of cell survival genes that are involved in promoting cellcycle progression and cellular transformation and in preventing apoptosis, as well as specifically involved in liver regeneration (Haga et al., 2005; Li et al., 2002).”
BackgroundNuclear Receptor-Dependent Bile Acid Signaling Is Required for Normal Liver Regeneration
Huang, W., Ma, K., Zhang, J., Qatanani, M., Cuvillier, J., Liu, J., Dong, B., Huang, X., & Moore, D. D. (2006) · Science · doi:10.1126/science.1121435 · Cited by 645
Met provides essential signals for liver regeneration
Borowiak, M., Garratt, A. N., Wüstefeld, T., Strehle, M., Trautwein, C., & Birchmeier, C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403412101 · Cited by 497
Molecular physiology of bile acid signaling in health, disease, and aging
Perino, A., Demagny, H., Velazquez-Villegas, L., & Schoonjans, K. (2021) · Physiological Reviews · doi:10.1152/physrev.00049.2019 · Cited by 481
Transcription Factors in Liver Development, Differentiation, and Regeneration
Costa, R. H., Kalinichenko, V. V., Holterman, A. L., & Wang, X. (2003) · Hepatology · doi:10.1016/j.hep.2003.09.034 · Cited by 408
The EGF receptor is required for efficient liver regeneration
Natarajan, A., Wagner, B., & Sibilia, M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704126104 · Cited by 320
Subramaniam, A., Shanmugam, M. K., Perumal, E., Li, F., Nachiyappan, A., Dai, X., Swamy, S. N., Ahn, K. S., Kumar, A. P., Tan, B. K. H., et al. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.10.002 · Cited by 284
“between the Alb+and Alb- STAT3 fl/fl livers is smaller at about 3-fold [150].”
BackgroundRegulation of liver regeneration by growth factors and cytokines
Böhm, F., Köhler, U. A., Speicher, T., & Werner, S. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000085 · Cited by 285
“A more severe defect in hepatocyte proliferation following PH was observed in another liver-specific Stat3 knockout strain in which Cre expression was driven by the albumin promoter (Li et al, 2002).”
BackgroundCytokines, STATs and liver disease.
Gao, B. (2005) · PubMed · Cited by 274
Signal Transducer and Activator of Transcription 3 in Liver Diseases: A Novel Therapeutic Target
Wang, H., Lafdil, F., Kong, X., & Gao, B. (2011) · International Journal of Biological Sciences · doi:10.7150/ijbs.7.536 · Cited by 270
“Rapid activation of STAT3 has been well-documented during liver regeneration after PHx or liver injury [59,84-86].”
BackgroundInteraction of staphylococci with bone
Wright, J. A., & Nair, S. P. (2009) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2009.10.003 · Cited by 268
Mao, S. A., Glorioso, J. M., & Nyberg, S. L. (2014) · Translational research · doi:10.1016/j.trsl.2014.01.005 · Cited by 260
“Studies in liver-specific stat3null mice demonstrate a significant contribution of the IL-6-induced STAT3 pathway to immediate-early gene expression.(35) This observed decline in immediateearly gene expression in the stat3-null mice was similar but not identical to the IL-6 knockout mice gene expression.”
Principles of Liver Regeneration and Growth Homeostasis
Michalopoulos, G. K. (2012) · Comprehensive physiology · doi:10.1002/cphy.c120014 · Cited by 278
Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms
Haga, S., Terui, K., Zhang, H. Q., Enosawa, S., Ogawa, W., Inoue, H., Okuyama, T., Takeda, K., Akira, S., Ogino, T., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17970 · Cited by 237
“Though targeted disruption of the Stat3 gene actually leads to early embryonic lethality (10), studies have been done using mice with conditional knockout (liver, lymphocyte) of Stat3 (10, 11).”
BackgroundInfluentialThe STAT3 isoforms α and β have unique and specific functions
Maritano, D., Sugrue, M. L., Tininini, S., Dewilde, S., Strobl, B., Fu, X., Murray-Tait, V., Chiarle, R., & Poli, V. (2004) · Nature Immunology · doi:10.1038/ni1052 · Cited by 234
“with transgenic mice that express Cre recombinase under the control of the liver-specific Alb promoter (called Alb Cre here”
BackgroundSelf-citationKnockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells
Konnikova, L., Kotecki, M., Kruger, M. M., & Cochran, B. (2003) · BMC Cancer · doi:10.1186/1471-2407-3-23 · Cited by 219
“Due to the transient nature of cytokine and growth factor signaling and the presence of proteins such as SOCS, suppressor of cytokine signaling, and PIAS, protein inhibitor of activated STAT, that inhibit of STAT3 signaling, STAT3 activation under normal physiological conditions is transient, lasting anywhere from sev…”
Hepatoprotection via the IL-6/Stat3 pathway
Taub, R. A. (2003) · Journal of Clinical Investigation · doi:10.1172/jci19974 · Cited by 220
“Conditional Stat3 knockout mice have been used to show that Stat3 is an important component of the IL-6 response during liver regeneration and the acute-phase response, but Stat3 does not account for all of the effects of IL-6, particularly those that are mediated by MAPK activation (14).”
Self-citationFang, Y., Gupta, V., Karra, R., Holdway, J. E., Kikuchi, K., & Poss, K. D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309810110 · Cited by 190
Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-γ)
Sun, R., & Gao, B. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.08.055 · Cited by 187
Cui, Y., Hosui, A., Sun, R., Shen, K., Gavrilova, O., Chen, W., Cam, M. C., Gao, B., Robinson, G. W., & Hennighausen, L. G. (2007) · Hepatology · doi:10.1002/hep.21713 · Cited by 184
Horiguchi, N., Wang, L., Mukhopadhyay, P., Park, O., Jeong, W. I., Lafdil, F., Osei‐Hyiaman, D., Moh, A., Fu, X. Y., Pacher, P., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.01.016 · Cited by 180
Platelets Promote Liver Regeneration in Early Period after Hepatectomy in Mice
Murata, S., Ohkohchi, N., Matsuo, R., Ikeda, O., Myronovych, A., & Hoshi, R. (2007) · World Journal of Surgery · doi:10.1007/s00268-006-0772-3 · Cited by 177
STAT proteins – Key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver
Gao, B., Wang, H., Lafdil, F., & Feng, D. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.01.029 · Cited by 180
“For example, inhibition of hepatic STAT3, mediated through STAT3 or gp130 deletion, reduced liver regeneration after partial hepatectomy [60,61,69,70].”
BackgroundMethodSeki, E., Tsutsui, H., Iimuro, Y., Naka, T., Son, G., Akira, S., Kishimoto, T., Nakanishi, K., & Fujimoto, J. (2005) · Hepatology · doi:10.1002/hep.20603 · Cited by 176
Acute inflammation stimulates a regenerative response in the neonatal mouse heart
Han, C., Nie, Y., Lian, H., Liu, R., He, F., Huang, H., & Hu, S. (2015) · Cell Research · doi:10.1038/cr.2015.110 · Cited by 179
The roles of innate immune cells in liver injury and regeneration.
Dong, Z., Wei, H., Sun, R., & Tian, Z. (2007) · PubMed · Cited by 167
Walz, C., Ahmed, W. B., Lazarides, K., Betancur, M., Patel, N. K., Hennighausen, L. G., Zaleskas, V. M., & Etten, R. A. V. (2012) · Blood · doi:10.1182/blood-2011-12-397554 · Cited by 179
“Jude Children's Research Hospital, Memphis TN).(25)”
Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3
Riehle, K. J., Campbell, J. S., McMahan, R. S., Johnson, M. M., Beyer, R. P., Bammler, T. K., & Fausto, N. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20070820 · Cited by 161
Nakamura, K., Nonaka, H., Saito, H., Tanaka, M., & Miyajima, A. (2004) · Hepatology · doi:10.1002/hep.20086 · Cited by 157
Waris, G., Turkson, J., Hassanein, T., & Siddiqui, A. (2005) · Journal of Virology · doi:10.1128/jvi.79.3.1569-1580.2005 · Cited by 156
“It is generally believed that STAT-3 is involved in liver regeneration and growth regulation ( 28 ), but its role in HCV replication has not been reported.”
BackgroundRetractedMoh, A., Iwamoto, Y., Chai, G.-X., Zhang, S. S.-M., Kano, A., Yang, D. D., Zhang, W., Wang, J., Jacoby, J. J., Gao, B., et al. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700630 · Cited by 147
“01 between the L-Stat3 / and Stat3f/+ mice. www.laboratoryinvestigation.org | Laboratory Investigation | Volume 87 October 2007 1023 0 10 20 30 40 50 60 70 24 40 48 72 Time after PH (hr) B rd U p os iti ve n uc le i ( % ) * WT L-Stat3-/- DAPI Brdu Merge 3 days 60 days WT L-Stat3-/- Figure 4 Liver regeneration after PH…”
InfluentialSchattenberg, J. M., Galle, P. R., & Schuchmann, M. (2006) · Liver International · doi:10.1111/j.1478-3231.2006.01324.x · Cited by 144
“TNF-mediated regeneration involves activation of IL-6 and STAT3 (37, 38).”
BackgroundMassive Liver Growth in Mice Induced by Systemic Interleukin 6 Administration
Zimmers, T. A., McKillop, I. H., Pierce, R. H., Yoo, J.-Y., & Koniaris, L. G. (2003) · Hepatology · doi:10.1053/jhep.2003.50318 · Cited by 140
Li, W.-C., Ye, S., Sun, R., Liu, Y., Tang, Z., Kim, Y., Karras, J. G., & Zhang, H. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0484 · Cited by 139
Self-citationRajendran, P., Ong, T. H., Chen, L., Li, F., Shanmugam, M. K., Vali, S., Abbasi, T., Kapoor, S., Sharma, A. K., Kumar, A. P., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1123 · Cited by 136
“Also, conditional STAT3 knock-out in different organs and tissues have been developed by various groups (62).”
BackgroundFujiyoshi, M., & Ozaki, M. (2010) · Journal of Hepato-Biliary-Pancreatic Sciences · doi:10.1007/s00534-010-0304-2 · Cited by 129
“To elucidate the mechanisms by which STAT3 regulates proliferation, liver-specific STAT3-deficient mice were created [35] because systemic STAT3 deficiency was lethal in early embryonic stages [36].”
BackgroundMatsuo, R., Nakano, Y., & Ohkohchi, N. (2011) · Annals of Surgery · doi:10.1097/sla.0b013e318211caf8 · Cited by 122
Identification of Transcriptional Networks during Liver Regeneration
White, P., Brestelli, J. E., Kaestner, K. H., & Greenbaum, L. E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410844200 · Cited by 120
Cytokines in alcoholic liver disease
An, L., Wang, X., & Cederbaum, A. I. (2012) · Archives of Toxicology · doi:10.1007/s00204-012-0814-6 · Cited by 116
Concerted Functions of Gab1 and Shp2 in Liver Regeneration and Hepatoprotection
Bard-Chapeau, E. A., Yuan, J., Droin, N. M., Long, S., Zhang, E. E., Nguyen, T. V., & Feng, G. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02253-05 · Cited by 117
“Activation of Stat3 has been shown to contribute to hepatocyte proliferation and liver regeneration posthepatectomy (7, 25).”
BackgroundMolecular Mechanism of Liver Development and Regeneration
Tanimizu, N., & Miyajima, A. (2007) · International review of cytology · doi:10.1016/s0074-7696(06)59001-1 · Cited by 120
Desbois‐Mouthon, C., Wendum, D., Cadoret, A., Rey, C., Leneuve, P., Blaise, A., Housset, C., Tronche, F., Bouc, Y. L., & Holzenberger, M. (2006) · The FASEB Journal · doi:10.1096/fj.05-4704fje · Cited by 116
Diesen, D. L., & Kuo, P. C. (2009) · Journal of Surgical Research · doi:10.1016/j.jss.2009.09.019 · Cited by 112
“The NOS inhibitors, aminoguanidine and L-NMMA, demonstrate the need for NO in DNA synthesis [21], while other factors, including cytokine IL-6, TNF-α, NF-κB, and STAT3, also appear to be important in liver regeneration [2,29,33,36,97,169].”
BackgroundSun, C., Gao, W., Liu, J., Cheng, H., & Hao, J. (2020) · Respiratory Research · doi:10.1186/s12931-020-01477-y · Cited by 111
Leu, J. I.-J., Crissey, M. A. S., Craig, L. E., & Taub, R. A. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.4.1251-1259.2003 · Cited by 108
“Regaining of liver mass despite deficient DNA synthesis is a general phenomenon in animal models that are defective in liver regeneration that most likely results from hypertrophy of hepatocytes despite G1/S arrest (4, 9, 20 , 38).”
BackgroundSelf-citationHaga, S., Ogawa, W., Inoue, H., Terui, K., Ogino, T., Igarashi, R., Takeda, K., Akira, S., Enosawa, S., Furukawa, H., et al. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.03.027 · Cited by 108
“In liver-specific STAT3-KO (LS3-KO) mice, no abnormalities of liver development or structure were observed, but they showed reduced mitogenic response following PH [19].”
BackgroundPregnane X receptor is essential for normal progression of liver regeneration†
Dai, G., He, L., Bu, P., & Wan, Y. Y. (2008) · Hepatology · doi:10.1002/hep.22129 · Cited by 114
Fibroblast growth factor 15 deficiency impairs liver regeneration in mice
Kong, B., Huang, J., Zhu, Y., Li, G., Williams, J. A. R., Shen, S., Aleksunes, L. M., Richardson, J. R., Apte, U. M., Rudnick, D. A., et al. (2014) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00337.2013 · Cited by 103
“STAT3 has been shown to be critical in liver regeneration (7, 18).”
Ozaki, M. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.10.007 · Cited by 103
Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip
Goto, K., Suarez, A. A. R., Wrensch, F., Baumert, T. F., & Lupberger, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093057 · Cited by 108
“Similarly to EGFR, STAT3 plays a central role in the tight regulation of this process, as observed in animal models of partial hepatectomy [66].”
BackgroundCampbell, J. S., Riehle, K. J., Brooling, J. T., Bauer, R. L., Mitchell, C., & Fausto, N. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.4.2522 · Cited by 100
Liao, Y., Shikapwashya, O., Shteyer, E., Dieckgraefe, B. K., Hruz, P. W., & Rudnick, D. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407969200 · Cited by 97
p21 is required for dextrose-mediated inhibition of mouse liver regeneration #
Weymann, A., Hartman, E., Gazit, V. A., Wang, C., Glauber, M., Turmelle, Y. P., & Rudnick, D. A. (2009) · Hepatology · doi:10.1002/hep.22979 · Cited by 94
Adiponectin Signaling Pathways in Liver Diseases
Gamberi, T., Magherini, F., Modesti, A., & Fiaschi, T. (2018) · Biomedicines · doi:10.3390/biomedicines6020052 · Cited by 98
“In particular, the activation of the JAK-STAT3 pathway by IL-6 plays a key role in liver regeneration [92].”
BackgroundDectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways
Seifert, L., Deutsch, M., Alothman, S., Alqunaibit, D., Werba, G., Pansari, M., Pergamo, M., Ochi, A., Torres-Hernandez, A., Levie, E., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.058 · Cited by 95
“These cytokines, in turn, induce the phosphorylation of STAT3 in hepatocytes, leading to their proliferation (Li et al., 2002).”
BackgroundLiver Regeneration is Impaired in Lipodystrophic Fatty Liver Dystrophy Mice
Gazit, V. A., Weymann, A., Hartman, E., Finck, B. N., Hruz, P. W., Tzekov, A., & Rudnick, D. A. (2010) · Hepatology · doi:10.1002/hep.23920 · Cited by 93
JAK/STAT signalling mediates cell survival in response to tissue stress
Fortezza, M. L., Schenk, M., Cosolo, A., Kolybaba, A. M., Grass, I., & Classen, A.-K. (2016) · Development · doi:10.1242/dev.132340 · Cited by 89
“…for regeneration in tissues as diverse as the grasshopper leg to the mouse liver (Yamada et al., 1997; Bando et al., 2013; Cressman et al., 1996; Li et al., 2002; Wuestefeld et al., 2003; Zhao et al., 2014), dissecting the function of this highly conserved pathway is essential for our…”
BackgroundSingh, A. K., Rooge, S. B., Varshney, A., et al. (2017) · Hepatology · doi:10.1002/hep.29690 · Cited by 91
Control of Growth During Regeneration
Sun, G., & Irvine, K. D. (2014) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-391498-9.00003-6 · Cited by 93
Otu, H. H., Naxerova, K., Ho, K. J., Can, H., Nesbitt, N. T., Libermann, T. A., & Karp, S. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m608441200 · Cited by 90
Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2
Cheng, N., Kim, K.-H., & Lau, L. F. (2022) · JCI Insight · doi:10.1172/jci.insight.158207 · Cited by 87
Sun, R., Tian, Z., Kulkarni, S., & Gao, B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.9.5648 · Cited by 86
“Studies from liver-specific knockout mice suggest that IL-6/gp130/ STAT3 promote cell proliferation (13) and protect against liver injury induced by partial hepatectomy, (14), injection of CCl4 (15), or LPS (16).”
BackgroundMarshall, K. M., He, S., Zhong, Z., Atkinson, C., & Tomlinson, S. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20131902 · Cited by 86
“IL-6 expression is dependent on TNF-induced NF-B activation, and IL-6–induced activation of STAT3 plays a role in cell cycle progression (Cressman et al., 1996; Yamada et al., 1997; Li et al., 2002; Blindenbacher et al., 2003).”
BackgroundRole of Growth Hormone (GH) in Liver Regeneration
Pennisi, P. A., Kopchick, J. J., Thorgeirsson, S. S., LeRoith, D., & Yakar, S. (2004) · Endocrinology · doi:10.1210/en.2004-0655 · Cited by 85
“After partial hep- atectomy, the activation of cytokine and growth factor signaling pathways leads to the induction of transcription factor complexes such as nuclear factor- B, c-Myc, signal transducer and activator of transcription-3 (STAT3), cAMPresponsive element modulator, and activating protein-1 (1, 4–9).”
BackgroundInfluentialSasso, G. L., Celli, N., Caboni, M., Murzilli, S., Salvatore, L., Morgano, A., Vacca, M., Pagliani, T., Parini, P., & Moschetta, A. (2009) · Hepatology · doi:10.1002/hep.23436 · Cited by 84
Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses
Liu, Y., Shao, M., Wu, Y., Cheng, Y., Jiang, S., Liu, J., Dai, J., Liu, Y., Li, J. X., Jia, W., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.10.022 · Cited by 86
“IL-6 activates the JAKs/STAT3 pathway [11], and STAT3 activation plays a crucial part in hepatocyte proliferation during liver regenerative responses [12–14].”
BackgroundGene Deletions and Amplifications in Human Hepatocellular Carcinomas
Nalesnik, M. A., Tseng, G. C., Ding, Y., Xiang, G., Zheng, Z., Yu, Y., Marsh, J. W., Michalopoulos, G. K., & Luo, J. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.12.021 · Cited by 80
“Of interest, STAT3 is a major component of the signaling machinery involved in the entry of hepatocytes into the S phase during liver regeneration.(49) The activation of STAT3 is seen within 1 to 3 hours after partial hepatectomy.”
BackgroundThe Role of Autophagy for the Regeneration of the Aging Liver
Xu, F., Hua, C., Tautenhahn, H., Dirsch, O., & Dahmen, U. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103606 · Cited by 81
S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy
Espeillac, C., Mitchell, C., Celton‐Morizur, S., Chauvin, C., Koka, V., Gillet, C., Albrecht, J. H., Desdouets, C., & Pende, M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44203 · Cited by 84
Yang, S., Wang, S., Wu, C., Yeh, Y., Chai, C., Chunag, S.-C., Sheen, M., & Lee, K.-T. (2006) · Journal of Clinical Pathology · doi:10.1136/jcp.2006.036970 · Cited by 78
Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A
Chen, L., Zeng, Y., Yang, H., Lee, T. D., French, S. W., Corrales, F. J., García–Trevijano, E. R., Avila, M. A., Mato, J. M., & Lu, S. C.-L. (2004) · The FASEB Journal · doi:10.1096/fj.03-1204fje · Cited by 78
“STAT-3 is a known downstream target of IL-6 that is also critical for normal liver regeneration to occur (26).”
BackgroundSu, T.-H., Shiau, C.-W., Jao, P., Liu, C.-H., Liu, C.-J., Tai, W.-T., Jeng, Y.-M., Yang, H.-C., Tseng, T.-C., Huang, H.-P., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1507499112 · Cited by 78
“In our study, we consistently confirmed the antifibrotic effect of sorafenib and further verified that sorafenib inhibited the STAT3 pathway and downstream cyclin D1 and Mcl-1 expression, which are involved in the cell-cycle regulation and apoptosis (25).”
Backgroundda Silva, C. G., Studer, P., Skroch, M., Mahiou, J., Minussi, D. C., Peterson, C. R., Wilson, S. W., Patel, V. I., Ma, A., Csizmadia, E., et al. (2013) · Hepatology · doi:10.1002/hep.26197 · Cited by 77
“In turn, IL-6 binds to its receptor, activating the JAK/STAT3 (signal transducer and activator of transcription 3) pathway to promote hepatocyte proliferation.3 Accordingly, the superagonistic IL-6/soluble IL-6R fusion protein enhances LR.4 In contrast, mice with targeted disruption of IL-6 demonstrate impaired regene…”
BackgroundInfluentialStat3 is required for the development of skin cancer
Pedranzini, L., Leitch, A., & Bromberg, J. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22800 · Cited by 78
“been shown that phosphorylated Stat1 levels are markedly enhanced in Stat3 null hepatocytes (23).”
BackgroundAdvances in the regulation of liver regeneration
Jia, C. (2011) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/egh.10.87 · Cited by 75
Terui, K., Enosawa, S., Haga, S., Zhang, H. Q., Kuroda, H., Kouchi, K., Matsunaga, T., Yoshida, H., Engelhardt, J. F., Irani, K., et al. (2004) · Journal of Hepatology · doi:10.1016/j.jhep.2004.08.019 · Cited by 76
“The studies using liver-specific conditional knockout mice have indicated that Stat3 is an important initiator of hepatocellular proliferation [20] [21] [22].”
Toll-like receptors in acute liver injury and regeneration
Chen, Y., & Sun, R. (2011) · International Immunopharmacology · doi:10.1016/j.intimp.2011.04.023 · Cited by 75
Mair, M., Zollner, G., Schneller, D., Musteanu, M., Fickert, P., Gumhold, J., Schuster, C., Fuchsbichler, A., Bilban, M., Tauber, S., et al. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.02.049 · Cited by 75
Self-citationNucleus, mitochondrion, or reticulum? STAT3 à La Carte
Avalle, L., & Poli, V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092820 · Cited by 74
“regeneration [9,10], the stimulation of B lymphocytes differentiation [11], the regulation of the activity of many hematopoietic cells subsets [12–17], the induction of lysosome-mediated apoptosis during mammary gland involution [18], the protection from apoptosis and heart infarction [19], and the maintenance of plur…”
BackgroundSelf-citationDistinctive role of inflammation in tissue repair and regeneration
Choi, B., Lee, C., & Yu, J. (2023) · Archives of Pharmacal Research · doi:10.1007/s12272-023-01428-3 · Cited by 77
Naseem, S., Hussain, T., & Manzoor, S. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.01.002 · Cited by 72
Wen, Y., Feng, D., Wu, H., Liu, W., Li, H., Wang, F., Xia, Q., Gao, W., & Kong, X. (2015) · International Journal of Biological Sciences · doi:10.7150/ijbs.12118 · Cited by 75
“In OPN-/mice, the expression of all three of these genes was repressed due to the reduced activation of the Stat3 pathway, which is the key process that activates hepatocytes to enter the mitosis [35].”
BackgroundIL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: Regulation by SOCS3
Sun, R., Jaruga, B., Kulkarni, S., Sun, H., & Gao, B. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.10.171 · Cited by 73
Yin, S., Wang, H., Park, O., Wei, W., Shen, J., & Gao, B. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.01.001 · Cited by 69
“Since hepatic STAT3 has been shown to play an important role in promoting liver regeneration, 13–15 we hypothesized that enhanced STAT3 may contribute to the increased liver regeneration in IL-10 (cid:1) / (cid:1) mice.”
BackgroundFurchtgott, L., Chow, C. C., & Periwal, V. (2009) · Biophysical Journal · doi:10.1016/j.bpj.2009.01.061 · Cited by 72
Sakamori, R., Takehara, T., Ohnishi, C., Tatsumi, T., Ohkawa, K., Takeda, K., Akira, S., & Hayashi, N. (2007) · Hepatology · doi:10.1002/hep.21837 · Cited by 71
Cell Signals Influencing Hepatic Fibrosis
Cong, M., Iwaisako, K., Jiang, C., & Kisseleva, T. (2012) · International Journal of Hepatology · doi:10.1155/2012/158547 · Cited by 74
“Stat3 regulates the expression of cyclin D1 [117], which is required for hepatocyte proliferation [118].”
BackgroundDu, Y. N., Chou, C., Klimstra, D. S., & VARMUS, H. E. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1114022108 · Cited by 67
“Conditional STAT3 knockout mice have been used to show that STAT3 is important for the function of interleukin-6 (IL-6) in liver regeneration (19).”
BackgroundDynamic recruitment of microRNAs to their mRNA targets in the regenerating liver
Schug, J., McKenna, L. B., Walton, G., Hand, N., Mukherjee, S., Essuman, K., Shi, Z., Gao, Y., Markley, K., Nakagawa, M., et al. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-264 · Cited by 66
“their targets in the regenerating liver, we plotted total gene expression and RISC recruitment for two clusters of genes known to be important in the regenerative process after partial hepatectomy [37].”
BackgroundWANG, X., Bhattacharyya, D., Dennewitz, M. B., Kalinichenko, V. V., ZHOU, Y., Lepe, R., & Costa, R. H. (2003) · Gene Expression · doi:10.3727/000000003108749044 · Cited by 67
“Consistent with this finding, regenerating TTR-FoxM1B TG livers exhibited in1), which are required to mediate hepatocyte proliferation during liver regeneration (29,40) and the MMP- creased expression of Stat3 mRNA, suggesting that”
BackgroundCREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice
Hu, Z., Han, Y., Liu, Y., Zhao, Z., Ma, F., Cui, A., Zhang, F., Liu, Z., Xue, Y., Bai, J., et al. (2020) · Hepatology · doi:10.1002/hep.30919 · Cited by 65
JAK-STAT signaling in hepatic fibrosis
Mair, M. (2011) · Frontiers in bioscience · doi:10.2741/3886 · Cited by 64
“When mice were treated with prolactin (PRL) and subjected to PHx, they displayed premature cell cycle entry of hepatocytes leading to increased numbers of proliferating liver cells when compared to untreated mice (143).”
BackgroundInfluentialWang, H., Zhang, H., Zhang, Z., Huang, B., Cheng, X., Wang, D., la Gahu, Z., Xue, Z., Da, Y., Li, D., et al. (2016) · Scientific Reports · doi:10.1038/srep19445 · Cited by 63
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 ›
Are you an author, or do you see a problem with this page? Request a review
