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

Sudhakar Kalakonda, Shreeram C. Nallar, Sausan Jaber, Susan K. Keay, Ellen Rorke, Raghava Munivenkatappa, Daniel J. Lindner, Gary M. Fiskum, Dhananjaya V. Kalvakolanu

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19), a STAT3-inhibitory protein, was isolated as a growthsuppressive 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.

Original languageEnglish (US)
Pages (from-to)E4213-E4222
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - Nov 5 2013
Externally publishedYes


  • Cytokines
  • Glucose metabolism
  • Immune response
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • General


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