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.
Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):E4213-22. doi: 10.1073/pnas.1303760110. Epub 2013 Oct 21.
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.
基因相关的视黄酸-干扰素诱导的死亡率-19（GRIM-19），是一种 STAT3 抑制蛋白，被分离出来作为生长抑制基因产物，使用全基因组表达敲低筛选。我们和其他人已经表明，在各种原发性人类癌症中，GRIM-19 基因的表达缺失和突变的发生，表明其作为肿瘤抑制因子的潜在作用。为了帮助研究其在体内肿瘤发展中的作用，我们生成了一种遗传修饰的小鼠，其中 Grim-19 可以条件性失活。在皮肤中删除 Grim-19 显著增加了小鼠对化学致癌作用的易感性，导致鳞状细胞癌的发展。这些肿瘤具有高 Stat3 活性和 Stat3 反应基因的表达增加。Grim-19 的缺失也导致线粒体电子传递功能障碍，这是由于电子传递链复合物组装失败以及涉及糖酵解的几个细胞基因的表达改变所致。令人惊讶的是，单个 Grim-19 基因的缺失足以促进致癌作用和侵袭性鳞状细胞癌的形成。这些观察结果强调了 GRIM-19 作为肿瘤抑制因子的关键作用。
