Identification of a structural motif in the tumor-suppressive protein GRIM-19 required for its antitumor activity.
We have previously isolated GRIM-19, a novel growth suppressor, using a genetic method. GRIM-19 ablates cell growth by inhibiting the transcription factor signal transducer and activator of transcription 3 (STAT3). Up-regulation of STAT3 and growth promotion were observed in a number of human tumors. Although the tumor-suppressive actions of GRIM-19 are known, the structural elements required for its antitumor actions are not understood. Mutational and protein sequence analyses identified a motif in the N terminus of GRIM-19 that exhibited similarity to certain RNA viral proteins. We show that disruption of specific amino acids within this motif cripples the antitumor actions of GRIM-19. These mutants fail to interact with STAT3 efficiently and consequently do not inhibit growth-promoting gene expression. More importantly, we show that a clinically observed mutation in the N terminus of GRIM-19 also weakened its interaction with STAT3 and antitumor action. Together, these studies identify a major role for the N terminus of GRIM-19 in mediating its tumor-suppressive actions.
Nallar
Shreeram C
SC
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Kalakonda
Sudhakar
S
Sun
Peng
P
Ohmori
Yoshihiro
Y
Hiroi
Miki
M
Mori
Kazumasa
K
Lindner
Daniel J
DJ
Kalvakolanu
Dhananjaya V
DV
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D050796:STAT3 Transcription Factor; D025521:Tumor Suppressor Proteins; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human