STAT3β, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription
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The 89-kDa STAT3 protein is a latent transcription factor which is activated in response to cytokines (interleukin (IL)-5 and -6) and growth factors (epidermal growth factor). Binding of IL-5 to its specific receptor activates JAK2 which leads to the tyrosine phosphorylation of STAT3 proteins. Here we report the cloning of a cDNA encoding a variant of the transcription factor STAT3 (named STAT3beta) which was isolated by screening an eosinophil cDNA library. Compared to wild-type STAT3, STAT3beta lacks an internal domain of 50 base pairs located near the C terminus. This splice product is a naturally occurring isoform of STAT3 and encodes a 80-kDa protein. We found by reconstitution of the human IL-5R in COS cells that like STAT3, STAT3beta is phosphorylated on tyrosine and binds to the pIRE from the ICAM-1 promoter after IL-5 stimulation. However, STAT3beta fails to activate a pIRE containing promoter in transient transfection assays. Instead, co-expression of STAT3beta inhibits the transactivation potential of STAT3. These results suggests that STAT3beta functions as a negative regulator of transcription.
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STAT3α and STAT3β arise from alternative splicing; STAT3α is 92 kDa and 770 amino acids, whereas STAT3β is 84 kDa and identical except that 55 C-terminal amino acids are replaced by a unique seven-amino-acid sequence.
“Two distinct STAT3 isoforms originating from alternative splicing have been described. STAT3α (92 kDa) is 770 amino acids in length, whereas STAT3β (84 kDa) is identical in sequence with the exception of 55 amino acids at the C-terminal tail that are replaced with a unique seven-amino-acid sequence (Figure 1A) [10,11].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [10]
Initial support for STAT3β acting as a dominant-negative regulator came with the repression and/or down-regulation of a number of recognized STAT3α target genes when STAT3β was overexpressed.
“Initial support for this came with the repression and/or down-regulation of a number of recognized STAT3α target genes when STAT3β was overexpressed [10,48].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [10]
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- Authors
- Caldenhoven, E., van Dijk, T. B., Solari, R., Armstrong, J., Raaijmakers, J. A. M., Lammers, J.-W. J., Koenderman, L., & de Groot, R. P.
- Affiliations
- University Medical Center Utrecht (NL)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-05
- Volume
- 271
- Issue
- 22
- Pages
- 13221-13227
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1495457417
- Cited by
- 373
- References
- 61
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 7 · 2019: 9 · 2018: 10 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 14 · 2013: 10 · 2012: 8
- FWCI
- 11.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- STAT3β, transcription factors, dominant negative regulation, IL-5 receptor, eosinophils, transactivation inhibition, cytokine signaling, epidermal growth factor
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Cell Line, Cloning, Molecular, DNA-Binding Proteins, Humans, Molecular Sequence Data, Phosphorylation, Repressor Proteins, RNA Splicing, Sequence Homology, Nucleic Acid, Transcription, Genetic, Tyrosine, Trans-Activators, DNA, Complementary, STAT3 Transcription Factor
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