Abstract
Introduction IFNs potently suppress tumor growth which is synergistically enhanced using cell differentiating agents such as retinoic acid (RA). Using a genome-wide knockdown screen, we have identified several novel tumor suppressive gene products regulated IFN/RA called, the Gene(s)-associated with Retinoid-Interferon induced Mortality. Here, we will discuss the tumor suppressive properties of GRIM-19, a novel gene discovered in this screen. Methods Genome-wide knock down screening for tumor suppressors, Protein: protein interactions, Oncogene-induced cytoskeletal protein modification, tumor growth and metastases in vivo. Results One of the novel genes isolated in the screen, GRIM-19, binds to STAT3 and inhibits growth-promoting gene transcription. It also promotes cell cycle arrest by interacting with the CDK inhibitor p16 Ink4a, a tumor suppressor. GRIM-19 also blocks oncogene induced cell motility, cytoskeletal remodeling, and tumor formation. We show that expression of GRIM-19 is lost and its gene is mutated in several human cancers. Tumor derived mutant GRIM-19 proteins lost their ability suppress constitutively active STAT3 and v-src oncogene induced cellular transformation and tumor growth and metastasis. In addition, GRIM-19 collaborates with other tumor suppressors like p53 for enforcing growth suppression. For example, disrupting HPV-E6 oncogene andE6AP (an ubiquitin ligase, which promotes the degradation of p53), GRIM-19 promotes the stability of p53 tumor suppressor. These observations show that GRIM-19 regulates multiple transcriptional and non-transcriptional processes for inhibiting tumor growth and collaborate with other tumor suppressor pathways. The biological effects of GRIM-19 gene disruption and relevance to tumor suppression and tumor pathology will be discussed. Conclusion GRIM-19 is a novel tumor suppressor induced by IFNs. It exerts both transcriptional and non-transcriptional effects to control cell growth. Mutations/loss of GRIM-19 expression promotes tumor growth.
Published Version
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