The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3.
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-beta- and retinoic acid-induced cell death, codes for a approximately 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.
Zhang
Jun
J
Greenebaum Cancer Center, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Yang
Jinbo
J
Roy
Sanjit K
SK
Tininini
Silvia
S
Hu
Jiadi
J
Bromberg
Jacqueline F
JF
Poli
Valeria
V
Stark
George R
GR
Kalvakolanu
Dhananjaya V
DV
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012694:Serine / Q000737:chemistry; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D016376:Oligonucleotides, Antisense; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D012694:Serine; D014212:Tretinoin; D016899:Interferon-beta; D004247:DNA; D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse; C439057:NDUFA13 protein, human