Tyrosine phosphorylation regulates manganese superoxide dismutase (MnSOD) RNA-binding protein activity and MnSOD protein expression.
All cells tested contain a cytosolic protein that binds to a defined region in the 3' untranslated region of manganese superoxide dismutase (MnSOD) RNA; both the MnSOD RNA-binding protein (MnSOD-BP) and the cis element are required for efficient translation of MnSOD RNA [Chung, D. J., Wright, A. E., and Clerch, L. B. (1997) Biochemistry 37, 16298-16306]. This study was designed to test the hypothesis that MnSOD-BP activity is regulated by phosphorylation. When cell extracts from whole rat lung or a rat lung fibroblast cell line, RFL-6, were treated in vitro with a protein tyrosine phosphatase, there was a 4-fold increase in MnSOD-BP activity indicating that MnSOD-BP activity was upregulated by tyrosine dephosphorylation. RFL-6 cells treated in cell culture with herbimycin A or genistein, inhibitors of protein tyrosine kinase, had significantly more MnSOD-BP activity than cells treated with diluent. In RFL-6 cells treated with herbimycin A, the increase in MnSOD-BP activity was associated with an increase in the level of MnSOD protein without a change in MnSOD mRNA concentration. We propose that the modulation of MnSOD protein expression by the tyrosine phosphorylation state of MnSOD-BP is a potential therapeutic target for increasing MnSOD activity during periods of oxidative stress.
Knirsch
L
L
Lung Biology Laboratory, Department of Pediatrics, Georgetown University School of Medicine, Washington, DC 20007, USA.
Clerch
L B
LB
D018829:Adhesins, Bacterial / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D008345:Manganese / Q000378:metabolism; D008667:Metalloproteins / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D015008:Yersinia enterocolitica / Q000201:enzymology
D018829:Adhesins, Bacterial; D004791:Enzyme Inhibitors; D008667:Metalloproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C064832:YadA protein, Yersinia; D014443:Tyrosine; D008345:Manganese; D013482:Superoxide Dismutase; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases