GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction.
Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic transcription factor that can be activated by cytokines and growth factors. Stat3 plays important roles in cell growth, anti-apoptosis and cell transformation, and is constitutively active in various cancers. We examined its potential regulators by yeast two-hybrid screening. GRIM-19, a gene product related to interferon-beta- and retinoic acid-induced cancer cell death, was identified and demonstrated to interact with Stat3 in various cell types. The interaction is specific for Stat3, but not for Stat1 and Stat5a. The interaction regions in both proteins were mapped, and the cellular localization of the interaction was examined. GRIM-19 itself co-localizes with mitochondrial markers, and forms aggregates at the perinulear region with co-expressed Stat3, which inhibits Stat3 nuclear translocation stimulated by epidermal growth factor (EGF). GRIM-19 represses Stat3 transcriptional activity and its target gene expression, and also suppresses cell growth in Src-transformed cells and a Stat3-expressing cell line. Our data suggest that GRIM-19 is a novel negative regulator of Stat3.
Lufei
Chengchen
C
Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609.
Ma
Jing
J
Huang
Guochang
G
Zhang
Tong
T
Novotny-Diermayr
Veronica
V
Ong
Chin Thing
CT
Cao
Xinmin
X
D016475:3T3 Cells; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000737:chemistry; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014212:Tretinoin; D004815:Epidermal Growth Factor; D016899:Interferon-beta; D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse; C439057:NDUFA13 protein, human; D042967:Electron Transport Complex I; C580719:Ndufa13 protein, rat