Identification and characterization of cis elements in the STAT3 gene regulating STAT3α and STAT3β messenger RNA splicing
Abstract
Signal transducer and activator of transcription 3 (STAT3) is an oncogene and a critical regulator of multiple cell-fate decisions, including myeloid cell differentiation. Two isoforms of STAT3 have been identified: alpha (p92) and beta (p83). These differ structurally in their C-terminal transactivation domains, resulting in distinct functional activities. The cis genetic elements that regulate the ratio of alpha to beta messenger RNA (mRNA) are unknown. In this study, cloning, sequencing, and splicing analysis of the human and murine STAT3 genes revealed a highly conserved 5' donor site for generation of both alpha and beta mRNA and distinct branch-point sequences, polypyrimidine tracts, and 3' acceptor sites (ASs) for each. The beta 3' AS was found to be located 50 nucleotides downstream of the alpha 3' AS in exon 23. Two additional cryptic 3' ASs (delta and epsilon) were also identified. Thus, we identified for the first time the cis regulatory sequences responsible for generation of STAT3 alpha and STAT3 beta mRNA.
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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 [11]
STAT3β lacks the transactivation domain due to alternative mRNA splicing, which confers prolonged nuclear retention compared with STAT3βΔ.
“This domain is missing in the major alternative isoform of STAT3, STAT3β, due to alternative mRNA splicing that shifts the reading frame and replaces the 55-amino-acid residue TAD with seven distinct residues that confer prolonged nuclear retention to STAT3β compared with STAT3βΔ (Shao et al., 2001).”
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 Shao et al., 2001
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Caldenhoven, E., van Dijk, T. B., Solari, R., Armstrong, J., Raaijmakers, J. A. M., Lammers, J.-W. J., Koenderman, L., & de Groot, R. P. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.22.13221 · Cited by 373 · see citing works
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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
“This domain is missing in the major alternative isoform of STAT3, STAT3b, due to alternativemRNA splicing that shifts the reading frame and replaces the 55-amino-acid residue TAD with seven distinct residues that confer prolonged nuclear retention to STAT3b compared with STAT3bD (Shao et al., 2001).”
MethodSelf-citationNg, I. H. W., Ng, D. C. H., Jans, D. A., & Bogoyevitch, M. A. (2012) · Biochemical Journal · doi:10.1042/bj20120941 · Cited by 63 · see citing works
- Authors
- Shao, H., Quintero, A. J., & Tweardy, D. J.
- Affiliations
- University of Pittsburgh (US)
- Baylor College of Medicine (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2001-12-15
- Volume
- 98
- Issue
- 13
- Pages
- 3853-3856
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2033872644
- Cited by
- 43
- References
- 1
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 3 · 2016: 2 · 2015: 4 · 2014: 5 · 2012: 2
- FWCI
- 0.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA086430, R01 CA72261, R01 CA86430, R01CA072261)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- STAT3, STAT3β, alternative splicing, cis-regulatory elements, polypyrimidine tract, isoform ratio, oncogenes, myeloid differentiation, transactivation domain
- MeSH terms
- Animals, Base Sequence, Cloning, Molecular, DNA-Binding Proteins, Gene Expression Regulation, Humans, Molecular Sequence Data, Regulatory Sequences, Nucleic Acid, RNA Splicing, RNA, Messenger, Trans-Activators, Mutagenesis, Site-Directed, Sequence Alignment, Gene Deletion, Immediate-Early Proteins, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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