The STAT3 isoforms α and β have unique and specific functions
Abstract
Signal transducer and activator of transcription 3 (STAT3) is the main mediator of interleukin 6 (IL-6)-type cytokine signaling. It exists in two isoforms: the full-length STAT3 alpha and the truncated STAT3 beta, generally thought to act as a dominant negative factor. To assess their relative functions, we ablated the expression of either isoform by gene targeting. We show here that in vivo STAT3 beta is not a dominant negative factor. Its expression can rescue the embryonic lethality of a STAT3-null mutation and it can by itself induce the expression of specific STAT3 target genes. Nevertheless, STAT3 alpha has nonredundant roles such as modulation of cellular responses to IL-6 and mediation of IL-10 function in macrophages.
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STAT3β spliceform expression rescues STAT3−/− embryonic lethality, highlighting key STAT3β-specific roles in development.
“A previous study demonstrating rescue of STAT3−/− embryonic lethality with STAT3β spliceform expression (i.e. in the absence of STAT3α) highlight key STAT3β-specific roles in development [15].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [15]
In vivo studies indicate a requirement for STAT3β during endotoxic assault, a requirement for STAT3α in IL-8 synthesis, and differential roles for STAT3α and STAT3β in anti-inflammatory responses.
“spliceform-specific functions have been indicated by various in vivo studies showing a requirement for STAT3β during endotoxic assault [16], but a requirement for STAT3α in IL-8 synthesis [17], as well as differential roles for STAT3α and STAT3β in anti-inflammatory responses [15].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [15]
STAT3β has been shown to initiate transcription of the p27Kip1 gene in myeloblastic cells, α1-anti-chymotrypsin and α2-macroglobulin in hepatocytes, and acute-phase genes in the liver during inflammation, and so can act as an up-regulator of transcription of specific gene sets.
“Furthermore, STAT3β has been shown to initiate transcription of the p27Kip1 gene in myeloblastic cells [51], α1-anti-chymotrypsin and α2-macroglobulin in hepatocytes [52], acute-phase genes in the liver during inflammation [15], and so can act as an up-regulator of transcription of specific gene sets.”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [15]
The ability of STAT3β to rescue STAT3−/− embryonic lethality indicates that STAT3β can perform at least some of the roles of STAT3α.
“The ability of STAT3β to rescue STAT3−/− embryonic lethality has clearly indicated that STAT3β can perform at least some of the roles of STAT3α [15].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [15]
In initial studies in Stat3β−/− MEFs, no changes in STAT3α phosphorylation in the absence of STAT3β were observed.
“In initial studies in Stat3β−/− MEFs, no changes in STAT3α phosphorylation in the absence of STAT3β were observed [15].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [15]
Manifestations of dextran sulfate sodium-induced colitis are more severe in STAT3Δβ/Δβ transgenic mice, which express only STAT3α, indicating that a STAT3 activity globally contributes to dextran sulfate sodium-induced colitis.
“Manifestations of dextran sulfate sodium–induced colitis were more severe in STAT3Δβ/Δβ transgenic mice, which express only STAT3α (Maritano et al., 2004; Marino et al., 2014), indicating that a STAT3 activity globally contributes to dextran sulfate sodium–induced colitis.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Maritano et al., 2004
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STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration
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“with transgenic mice that express Cre recombinase under the control of the liver-specific Alb promoter (called Alb Cre here”
BackgroundSelf-citationRole of Stat3 in Lipopolysaccharide-Induced IL-10 Gene Expression
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“In addition to tyrosine phosphorylation, STAT3also undergoes a variety of other post-translational modifications, including methylation, acetylation, ubiquitination, IFN-stimulated gene (ISG)-ylation, and small ubiquitin-related modifiers (SUMOs)-conjugation (SUMOylation) (Kojima et al., 2013; You et al., 2015; Zouein…”
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- Authors
- Maritano, D., Sugrue, M. L., Tininini, S., Dewilde, S., Strobl, B., Fu, X., Murray-Tait, V., Chiarle, R., & Poli, V.
- Affiliations
- University of Dundee (GB)
- Beth Israel Deaconess Medical Center (US)
- University of Turin (IT)
- Cancer Research UK (GB)
- Corresponding author
- Poli, Valeria
- Venue
- Nature Immunology
- Published
- 2004-03-14
- Volume
- 5
- Issue
- 4
- Pages
- 401-409
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W1601667381
- Cited by
- 234
- References
- 5
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 9 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 10 · 2019: 11 · 2018: 15 · 2017: 8 · 2016: 7 · 2015: 7 · 2014: 15 · 2013: 8 · 2012: 12
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- STAT3, isoform-specific function, dominant negative effect, IL-6 signaling, IL-10, macrophages, embryonic lethality, gene targeting, cytokine signaling
- MeSH terms
- Animals, DNA-Binding Proteins, Fertility, Genes, Lethal, Inflammation, Kidney, Liver, Lung, Mutation, Immunoblotting, Trans-Activators, Interleukin-6, Protein Isoforms, STAT3 Transcription Factor, Mice
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