Rapid activation of the stat3 transcription complex in liver regeneration
Abstract
Liver regeneration in response to partial hepatectomy is a physiological growth response observed in the intact animal. Understanding the early signals that trigger liver regeneration is of vital importance to understand the liver's response to injury. It has been observed that several growth factors and cytokines, including epidermal growth factor (EGF) and interleukin-6 (IL-6), can activate members of the signal transducers and activators of transcription (Stat) family of transcription factors resulting in tyrosine phosphorylation of these factors, nuclear translocation, and an active DNA binding transcriptional complex. Because Stat3 participates in the regulation of primary growth response genes, we wondered if it is induced in the early phase of liver regeneration. We found that Stat3 DNA-binding activity is increased in the remnant liver within 30 minutes of partial hepatectomy and peaks at more than 30-fold at 3 hours. This induction is not observed after sham surgery. The induction of Stat3 appears to be part of the initial response of the remnant liver to partial hepatectomy, because it occurs in the presence of cycloheximide-mediated protein synthesis blockade. Activation of Stat3 is unusual, because it extends beyond the immediate-early time period and remains near peak level at 5 hours posthepatectomy. Although insulin-treated H35 cells activate many of the same immediate-early genes as regenerating liver, Stat3 is not induced in these cells. Because Stat factors are known to be inactivated by protein tyrosine phosphatases (PTPase), we showed that a PTPase is able to eliminate the DNA binding of hepatic Stat3. It is likely that Stat3 contributes to the transcriptional activation of a subset of immediate-early genes that are induced over a prolonged time in the G1 phase of hepatic cells following partial hepatectomy. The identification of Stat3 as an early factor in liver regeneration provides clues to the activation of signal transduction pathways in the remnant liver within the first minutes to several hours after partial hepatectomy.
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A low level of STAT3/STAT1 heterodimer and an even lower level of STAT1 homodimer are observed in control livers.
“A low level of STAT3/STAT1 heterodimer as well as an even lower level of STAT1 homodimer band were also observed as we have reported previously (17”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [17]
STAT1 is the only STAT in addition to STAT3 that is activated during liver regeneration.
“STAT1 is the only STAT in addition to STAT3 that is activated during liver regeneration (17”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [17]
STAT-3 is activated after PH as the result of increased IL-6 levels, implicating both IL-6 and STAT-3 as part of the priming mechanism for hepatocyte proliferation.
“It has been demonstrated previously that STAT-3 is activated after PH as the result of increased IL-6 levels (8, 9, 16), implicating both IL-6 and STAT-3 as part of the priming mechanism for hepatocyte proliferation.”
From Expression of suppressors of cytokine signaling during liver regeneration (2001) · cites this paper as [16]
Robust STAT-3 DNA-binding activity is detected by 2 hours and rapidly disappears between 3 to 6 hours after PH.
“As has been demonstrated previously (8, 9, 16), robust STAT-3 DNA-binding activity is detected by 2 hours and rapidly disappears between 3 to 6 hours.”
From Expression of suppressors of cytokine signaling during liver regeneration (2001) · cites this paper as [16]
Only STAT-3 homodimers are seen after PH.
“Only STAT-3 homodimers are seen after PH (Figure 2c and ref. 16).”
From Expression of suppressors of cytokine signaling during liver regeneration (2001) · cites this paper as [16]
Several immediate early genes induced after partial hepatectomy are target genes of STAT3 and NF-kB.
“Several of these induced genes are target genes of signal transducer and activator of transcription (STAT)3 and nuclear factor kappa B (NFB), two transcription factors that are activated early during liver regeneration.5,6”
From Interleukin 6 Is Important for Survival After Partial Hepatectomy in Mice (2003) · cites this paper as [6]
IL-6-deficient mice display increased susceptibility to perioperative morbidity and mortality after partial hepatectomy.
“IL-6 -deficient mice display an increased susceptibility to perioperative morbidity and mortality after PH (Fig. 1).6”
From Interleukin 6 Is Important for Survival After Partial Hepatectomy in Mice (2003) · cites this paper as [6]
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- Authors
- Cressman, D. E., Diamond, R. H., & Taub, R.
- Affiliations
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Taub, Rebecca
- ORCID
- Taub, Rebecca
- Venue
- Hepatology
- Published
- 1995-05
- Volume
- 21
- Issue
- 5
- Pages
- 1443-1449
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2076822857
- Cited by
- 314
- References
- 1
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 10 · 2021: 3 · 2020: 11 · 2019: 8 · 2018: 7 · 2017: 7 · 2016: 5 · 2015: 6 · 2014: 14 · 2013: 11 · 2012: 15
- FWCI
- 9.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- STAT3, liver regeneration, partial hepatectomy, transcription factor activation, DNA-binding activity, protein tyrosine phosphatase, immediate early genes, signal transduction, remnant liver, epidermal growth factor, interleukin-6, G1 phase
- MeSH terms
- Animals, Base Sequence, Cell Line, DNA-Binding Proteins, Female, Gene Expression Regulation, Insulin, Liver, Liver Regeneration, Molecular Sequence Data, Rats, Inbred F344, Transcription, Genetic, Protein Biosynthesis, Molecular Probes, Trans-Activators, Protein Tyrosine Phosphatases, Immediate-Early Proteins, STAT3 Transcription Factor, Rats
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