Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability.
Deficiency of tristetraprolin (TTP), the prototype of the CCCH zinc finger proteins, results in a complex inflammatory syndrome in mice. Most aspects of the syndrome are secondary to excess circulating tumor necrosis factor (TNF)-alpha, a consequence of increased stability of TNF-alpha messenger RNA (mRNA) in TTP-deficient macrophages. TTP can bind directly to the AU-rich element in TNF-alpha mRNA, increasing its lability. Here we show that TTP deficiency also results in increased cellular production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and increased stability of its mRNA, apparently secondary to decreased deadenylation. Similar findings were observed in mice also lacking both types of TNF-alpha receptors, excluding excess TNF-alpha production as a cause of the increased GM-CSF mRNA levels and stability. TTP appears to be a physiological regulator of GM-CSF mRNA deadenylation and stability. (Blood. 2000;95:1891-1899)
Carballo
E
E
Office of Clinical Research and Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Lai
W S
WS
Blackshear
P J
PJ
D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003609:Dactinomycin / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013997:Time Factors; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016335:Zinc Fingers / Q000502:physiology
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D003609:Dactinomycin; D000249:Adenosine Monophosphate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor