title: Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice.
abstract: 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.
authors.affiliation: Departments of Microbiology and Immunology, Anesthesiology, Medicine, and Pathology, Greenebaum Cancer Center, Graduate Program in Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Kalakonda
authors.forename: Shreeram C
authors.initials: SC
authors.lastname: Nallar
authors.forename: Sausan
authors.initials: S
authors.lastname: Jaber
authors.forename: Susan K
authors.initials: SK
authors.lastname: Keay
authors.forename: Ellen
authors.initials: E
authors.lastname: Rorke
authors.forename: Raghava
authors.initials: R
authors.lastname: Munivenkatappa
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lindner
authors.forename: Gary M
authors.initials: GM
authors.lastname: Fiskum
authors.forename: Dhananjaya V
authors.initials: DV
authors.lastname: Kalvakolanu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D040461:Gene Components; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D017931:DNA Primers; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse
keywords: cytokines; glucose metabolism; immune response; oxidative phosphorylation