The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3 Journal Article
| Authors: | Zhang, J.; Yang, J.; Roy, S. K.; Tininini, S.; Hu, J.; Bromberg, J. F.; Poli, V.; Stark, G. R.; Kalvakolanu, D. V. |
| Article Title: | The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3 |
| Abstract: | GRIM-19 (gene associated with retinoid-IFN-induced mortality 19), isolated as a cell death activator in a genetic screen used to define mechanisms involved in IFN-β- and retinoic acid-induced cell death, codes for a ≈16-kDa protein that induces apoptosis in a number of cell lines. Antisense ablation of GRIM-19 caused resistance to cell death induced by IFN plus retinoic acid and conferred a growth advantage to cells. To understand the molecular bases for its cell death regulatory activity, we used a yeast two-hybrid screen and identified that the transcription factor STAT3 (signal transducer and activator of transcription 3) binds to GRIM-19. GRIM-19 inhibits transcription driven by activation of STAT3, but not STAT1. It neither inhibits the ligand-induced activation of STAT3 nor blocks its ability to bind to DNA. Mutational analysis indicates that the transactivation domain of STAT3, especially residue S727, is required for GRIM-19 binding. Because GRIM-19 does not bind significantly to other STATs, our studies identify a specific inhibitor of STAT3. Because constitutively active STAT3 up-regulates antiapoptotic genes to promote tumor survival, its inhibition by GRIM-19 also demonstrates an antioncogenic effect exerted by biological therapeutics. |
| Keywords: | controlled study; unclassified drug; human cell; dna-binding proteins; antineoplastic agent; protein domain; protein function; animals; mice; cell death; stat3 protein; apoptosis; cell growth; serine; protein protein interaction; protein binding; apoptosis regulatory proteins; antineoplastic activity; transfection; mutational analysis; gene activation; cytokines; dna; immune response; transcription regulation; amino acid sequence; eukaryota; oligonucleotide array sequence analysis; transactivation; ligands; stat3 transcription factor; plasmids; amino acid; protein structure, tertiary; upregulation; trans-activators; dna mutational analysis; up-regulation; tumor growth; tumor suppressor protein; two hybrid system; cell strain mcf 7; beta interferon; retinoic acid; oligonucleotides, antisense; two-hybrid system techniques; interferon-beta; inhibitor protein; tretinoin; nadh, nadph oxidoreductases; stat1 transcription factor; humans; human; priority journal; article; protein grim19; mink cell focus-forming virus |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 100 |
| Issue: | 16 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2003-08-05 |
| Start Page: | 9342 |
| End Page: | 9347 |
| Language: | English |
| DOI: | 10.1073/pnas.1633516100 |
| PUBMED: | 12867595 |
| PROVIDER: | scopus |
| PMCID: | PMC170920 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
