Tumor-derived Mutations in the Gene Associated with Retinoid Interferon-induced Mortality (GRIM-19) Disrupt Its Anti-signal Transducer and Activator of Transcription 3 (STAT3) Activity and Promote Oncogenesis
Open accessAbstract
The signal transducer and activator of transcription 3 (STAT3) protein is critical for multiple cytokine and growth factor-induced biological responses in vivo. Its transcriptional activity is controlled by a transient phosphorylation of a critical tyrosine. Constitutive activation of STAT3 imparts resistance to apoptosis, promotes cell proliferation, and induces de novo micro-angiogenesis, three of the six cardinal hallmarks of a typical cancer cell. Earlier we reported the isolation of GRIM-19 as a growth suppressor using a genome-wide expression knockdown strategy. GRIM-19 binds to STAT3 and suppresses its transcriptional activity. To understand the pathological relevance of GRIM-19, we screened a set of primary head and neck tumors and identified three somatic mutations in GRIM-19. Wild-type GRIM-19 suppressed cellular transformation by a constitutively active form of STAT3, whereas tumor-derived mutants L71P, L91P and A95T significantly lost their ability to associate with STAT3, block gene expression, and suppress cellular transformation and tumor growth in vivo. Additionally, these mutants lost their capacity to prevent metastasis. These mutations define a mechanism by which STAT3 activity is deregulated in certain human head and neck tumors.
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Activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.
“Conversely, activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [16]
The Abstract (page unavailable) reports that somatic GRIM-19 mutations impair its ability to inhibit STAT3, supporting genomic inactivation as one route to increased STAT3 activity. The Discussion (page unavailable) also identifies loss of STAT3 inhibitors as a possible cause of constitutive activation. The cited passages do not establish epigenomic inactivation of those inhibitors; the methylation mentioned in the Discussion concerns STAT protein modification, not epigenomic silencing. (LLM, conf=0.86)
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Cites
Function of Mitochondrial Stat3 in Cellular Respiration
Wegrzyn, J., Potla, R., Chwae, Y.-J., Sepuri, N. B. V., Zhang, Q., Koeck, T., Derecka, M., Szczepanek, K., Szelag, M., Gornicka, A., et al. (2009) · Science · doi:10.1126/science.1164551 · Cited by 1,014 · see citing works
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Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation
Yang, J., Chatterjee-Kishore, M., Staugaitis, S. M., Nguyen, H., Schlessinger, K., Levy, D. E., & Stark, G. R. (2005) · Cancer Research · doi:10.1158/0008-5472.939.65.3 · Cited by 405 · see citing works
Stat3 Orchestrates Tumor Development and Progression: The Achilles Heel of Head and Neck Cancers?
Masuda, M., Wakasaki, T., Suzui, M., Toh, S., Joe, A., & Weinstein, I. (2010) · Current Cancer Drug Targets · doi:10.2174/156800910790980197 · Cited by 60 · see citing works
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Research works printed but not linked: 3
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Critical analysis of the potential for targeting STAT3 in human malignancy
Grandis, J., & Peyser (2013) · OncoTargets and Therapy · doi:10.2147/ott.s47903 · Cited by 24 · see citing works
“These events do occur, however, as evinced by recently reported mutations in GRIM-19 that ablate its STAT3 inhibitory activity and promote tumor growth.(16) Many investigators have recently begun to focus on epigenomic silencing of tumor-suppressive proteins that normally downregulate STAT3, especially by promoter hyp…”
- Authors
- Nallar, S. C., Kalakonda, S., Lindner, D. J., Lorenz, R. R., Lamarre, E., Weihua, X., & Kalvakolanu, D. V.
- Affiliations
- University of Maryland, Baltimore (US)
- Cleveland Clinic (US)
- University of Science and Technology of China (CN)
- Corresponding author
- Kalvakolanu, Dhananjaya V.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 288
- Issue
- 11
- Pages
- 7930-7941
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3597830
- OpenAlex
- W2001570908
- Cited by
- 29
- References
- 4
- Citations by year
- 2022: 1 · 2021: 1 · 2018: 1 · 2017: 3 · 2016: 7 · 2015: 6 · 2014: 7 · 2013: 2
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA105005)
- National Cancer Institute (R01CA105005)
- 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 › TGF-β signaling in diseases
- Keywords
- GRIM-19, STAT3, somatic mutations, head and neck cancer, tumor suppressor, STAT3 phosphorylation, cell transformation, metastasis, gene knockdown, carcinogenesis
- MeSH terms
- Animals, Carcinoma, Squamous Cell, Gene Expression Regulation, Humans, Mice, Nude, Mouth Neoplasms, Mutation, NADH, NADPH Oxidoreductases, Neoplasm Metastasis, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Molecular Chaperones, Gene Expression Profiling, Electron Transport Complex I, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, Apoptosis Regulatory Proteins, Mice, Rats
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