Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19), a STAT3-inhibitory protein, was isolated as a growth-suppressive gene product using a genome-wide expression knockdown screen. We and others have shown a loss of expression and occurrence of mutations in the GRIM-19 gene in a v...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2013-11, Vol.110 (45), p.18035-18035
Hauptverfasser: Kalakonda, Sudhakar, Nallar, Shreeram C., Jaber, Sausan, Keay, Susan K., Rorke, Ellen, Munivenkatappa, Raghava, Lindner, Daniel J., Fiskum, Gary M., Kalvakolanu, Dhananjaya V.
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Sprache:eng
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Zusammenfassung:Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19), a STAT3-inhibitory protein, was isolated as a growth-suppressive gene product using a genome-wide expression knockdown screen. We and others have shown a loss of expression and occurrence of mutations in the GRIM-19 gene in a variety of primary human cancers, indicating its potential role as tumor suppressor. To help investigate its role in tumor development in vivo, we generated a genetically modified mouse in which Grim-19 can be conditionally inactivated. Deletion of Grim-19 in the skin significantly increased the susceptibility of mice to chemical carcinogenesis, resulting in development of squamous cell carcinomas. These tumors had high Stat3 activity and an increased expression of Stat3-responsive genes. Loss of Grim-19 also caused mitochondrial electron transport dysfunction resulting from failure to assemble electron transport chain complexes and altered the expression of several cellular genes involved in glycolysis. Surprisingly, the deletion of a single copy of the Grim-19 gene was sufficient to promote carcinogenesis and formation of invasive squamous cell carcinomas. These observations highlight the critical role of GRIM-19 as a tumor suppressor.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1303760110