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Updated: May 6, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice
Sudhakar Kalakonda1, Shreeram C Nallar, Sausan Jaber
1Departments 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.
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.
Insights
Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19) acts as a tumor suppressor. Loss of GRIM-19 promotes skin cancer development by increasing STAT3 activity and impairing mitochondrial function.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19) is a STAT3-inhibitory protein identified as a growth-suppressive gene.
- Loss of GRIM-19 expression and mutations are observed in various human cancers, suggesting its tumor suppressor function.
Purpose of the Study:
- To investigate the in vivo role of GRIM-19 in tumor development.
- To determine the consequences of GRIM-19 inactivation in a mouse model.
Main Methods:
- Generation of a genetically modified mouse model with conditional inactivation of the Grim-19 gene.
- Induction of chemical carcinogenesis in the skin of these mice.
- Analysis of tumor development, STAT3 activity, gene expression (including glycolysis-related genes), and mitochondrial function.
Main Results:
- Conditional deletion of Grim-19 in mouse skin significantly increased susceptibility to chemical carcinogenesis, leading to squamous cell carcinomas.
- Tumors exhibited elevated STAT3 activity and increased expression of STAT3-responsive genes.
- Loss of GRIM-19 resulted in mitochondrial electron transport chain dysfunction and altered expression of genes involved in glycolysis.
- Deletion of even a single copy of the Grim-19 gene promoted carcinogenesis and invasive tumor formation.
Conclusions:
- GRIM-19 functions as a critical tumor suppressor.
- Inactivation of GRIM-19 promotes skin carcinogenesis through STAT3 activation and metabolic dysfunction.
- These findings underscore the importance of GRIM-19 in preventing cancer development.
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