title: 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.
abstract: 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.
authors: Department of Microbiology and Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Shreeram C
authors: SC
authors: Nallar
authors: Department of Microbiology and Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Sudhakar
authors: S
authors: Kalakonda
authors: Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors: Daniel J
authors: DJ
authors: Lindner
authors: Head and Neck Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors: Robert R
authors: RR
authors: Lorenz
authors: Head and Neck Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors: Eric
authors: E
authors: Lamarre
authors: University of Science Technology, 230027 Hefei, China.
authors: Xiao
authors: X
authors: Weihua
authors: Department of Microbiology and Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: dkalvako@umaryland.edu.
authors: Dhananjaya V
authors: DV
authors: Kalvakolanu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042967:Electron Transport Complex I / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000378:metabolism; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D018832:Molecular Chaperones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse; C439057:NDUFA13 protein, human; D042967:Electron Transport Complex I; C580719:Ndufa13 protein, rat
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