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

• Published in: The Journal of biological chemistry 2013-03, Vol.288 (11), p.7930-7941
• Main Authors: Nallar, Shreeram C., Kalakonda, Sudhakar, Lindner, Daniel J., Lorenz, Robert R., Lamarre, Eric, Weihua, Xiao, Kalvakolanu, Dhananjaya V.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; Carcinoma, Squamous Cell - metabolism; Cell Growth; Cell Line, Tumor; Cell Proliferation; Cytokines/Interferon; Electron Transport Complex I - metabolism; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Molecular Bases of Disease; Molecular Chaperones - metabolism; Mouth Neoplasms - metabolism; Mutation; NADH, NADPH Oxidoreductases - metabolism; Neoplasm Metastasis; Rats; STAT3 Transcription Factor - metabolism; Transcription, Genetic; Transformation; Tumor Cell Biology; Tumor Metastases
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.440610

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. Background: Aberrantly active STAT3 promotes tumorigenesis. GRIM-19 binds to STAT3 and inhibits its growth promotion. Results: We identified three mutations in the GRIM-19 gene that failed to block STAT3-dependent gene expression and tumor development. Conclusion: GRIM-19 mutations unleash STAT3 activity to promote tumor growth. Significance: This study identifies a new mechanism by which normal cells acquire cancerous properties.