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Cited by 405Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesNF-κB Signaling Pathways

Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation

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Yang, Jinbo, Chatterjee-Kishore, Moitreyee, Staugaitis, Susan M., Nguyen, Hannah, Schlessinger, Karni, Levy, David E., Stark, George R.·2005·Cancer Research
DOI 10.1158/0008-5472.939.65.3
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Abstract

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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Crossref · 10.1158/0008-5472.939.65.3

Cites

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  • Nonpeptidic tyrosine kinase-targeted inhibitors have diminished efficacy because the inherent transcriptional activity of unphosphorylated STAT3 can drive MET and MRAS by binding NF-κB.

    “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]

    The Introduction reports that unphosphorylated STAT3 drives expression of MET and MRAS. The “STAT3 and Cancer” section discusses selecting drugs that target STAT3 dimers according to the mechanism active in a tumor, but does not report diminished efficacy of nonpeptidic tyrosine kinase-targeted inhibitors. The passages found do not establish that STAT3 drives these genes by binding NF-κB. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Targeted STAT3 degradation can completely inhibit the transcriptional activity of both dimerized and monomeric STAT3.

    “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]

    The Discussion (page not provided) describes transcriptional roles for STAT3 dimers and unphosphorylated STAT3. It does not establish that unphosphorylated STAT3 is monomeric, or test whether targeted degradation completely inhibits either form's transcriptional activity. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Basal STAT3 has been shown to have transcriptional activity under basal conditions.

    “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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Cites

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Research works printed but not linked: 2

  1. Reddy MVR, Chaturvedi P, Reddy EP. Src kinase mediated activation of STAT3 plays an essential role in the proliferation and oncogenicity of human breast, prostate and ovarian carcinomas. Proc AACR 1999; 40:376.
  2. Lou W, Ni Z, Dyer K, Tweardy DJ, Gao AC. Interleukin-6 induces prostate cancer cell growth accompanied by activation of STAT3 signaling pathway. Prostrate 2000;42:239-22.

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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)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2005-02-01
Volume
65
Issue
3
Pages
939-947
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.939.65.3
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
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
  • 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 › 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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