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Novel Roles of Unphosphorylated STAT3 in Oncogenesis and Transcriptional Regulation
Open accessAbstract
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated on tyrosine residue 705 in response to growth factors or cytokines to form activated homodimers that drive gene expression. Because the stat3 promoter has a binding site for STAT3 dimers, the amount of STAT3 protein increases when STAT3 is activated (e.g., in response to interleukin 6). Unphosphorylated STAT1 is known to drive the expression of certain genes. To explore the possibility of a similar role for the induced expression of unphosphorylated STAT3, we overexpressed either Y705F STAT3, which can not be phosphorylated on residue 705, or wild-type STAT3 in normal human mammary epithelial cells or STAT3-null mouse cells. The levels of many mRNAs were affected strongly by high levels of either form of STAT3. Some genes whose expression was increased by overexpressed STAT3, but not by activated STAT3 dimers, encode well-known oncoproteins (e.g., MRAS and MET). In many tumors, STAT3 is activated constitutively, and thus the unphosphorylated form is likely to be expressed highly, driving oncogene expression by a novel mechanism. In addition, expression of the stat3 gene is increased strongly in response to interleukin 6, and the high levels of unphosphorylated STAT3 that result drive a substantial late phase of gene expression in response to this cytokine. Thus, unphosphorylated STAT3, which activates gene expression by a novel mechanism distinct from that used by STAT3 dimers, is very likely to be an important transcription factor both in cancer and in responses to cytokines.
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“However, their efficacy is diminished because the inherent transcriptional activity of unphosphorylated STAT3 could also drive the expression of oncogenes such as MET and MRAS by binding to NF-κB (18–21).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [21]
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“Second, the targeted STAT3 degradation can completely inhibit the transcriptional activity of both dimerized and monomeric STAT3 (19, 21, 26).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [21]
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“and that basal STAT3 has been shown to have transcriptional activity under basal conditions [44,45]”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [44]
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Self-citation
Metadata
- Authors
- Yang, J., Chatterjee-Kishore, M., Staugaitis, S. M., Nguyen, H., Schlessinger, K., Levy, D. E., & Stark, G. R.
- Affiliations
- 1Molecular Biology and Departments of
- Cleveland Clinic (US)
- New York University (US)
- Venue
- Cancer Research
- Published
- 2005-02-01
- Volume
- 65
- Issue
- 3
- Pages
- 939-947
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2147314043
- Cited by
- 405
- References
- 38
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 15 · 2022: 14 · 2021: 14 · 2020: 16 · 2019: 13 · 2018: 20 · 2017: 18 · 2016: 20 · 2015: 19 · 2014: 22 · 2013: 29 · 2012: 24
- FWCI
- 12.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cleveland Clinic
- Johns Hopkins University
- National Institutes of Health
- School of Medicine, Indiana University
- National Cancer Institute (P01CA062220)
- National Institute of Allergy and Infectious Diseases (R01AI028900)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- STAT3, tyrosine 705 phosphorylation, carcinogenesis, transcriptional regulation, interleukin-6, cytokine response, oncoprotein, mineralocorticoid receptor antagonists, MET, constitutive STAT3 activation, gene expression, mammary epithelial cells
- MeSH terms
- Animals, DNA-Binding Proteins, Female, Gene Expression Regulation, Humans, Neoplasms, Oncogenes, Phosphorylation, Proto-Oncogene Proteins, RNA, Messenger, Trans-Activators, Interleukin-6, Gene Expression Regulation, Neoplastic, Receptors, Growth Factor, ras Proteins, Proto-Oncogene Proteins c-met, Monomeric GTP-Binding Proteins, Mammary Glands, Human, STAT3 Transcription Factor, Mice
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