Gene suppression by tristetraprolin and release by the p38 pathway.
Tristetraprolin (TTP) is a zinc finger protein that has been implicated in the control of tumor necrosis factor (TNF) mRNA stability. We show here that TTP protein has a suppressive effect on promoter elements from TNF-alpha and interleukin-8 and that lipopolysaccharide (LPS) stimulation can release this suppression. The release in LPS-stimulated cells was found to be primarily mediated by the p38 pathway because activation of p38 is sufficient to remove the suppressive effect of TTP. Indeed, TTP seems to be a direct substrate of p38 in vivo since it is an excellent substrate of p38 in vitro, and mutation of potential phosphorylation sites in TTP prevents release of the suppression imposed on TNF transcription. We found TTP protein to be present at low levels in the resting macrophage cell line RAW 264.7 and to be quickly induced after LPS stimulation. The kinetics of TTP induction suggests a potential role of TTP as an important player in switching off LPS-induced genes after induction. In conclusion, TTP plays an important role in maintaining gene quiescence, and this quenching effect on transcription can be released by p38 phosphorylation of TTP.
Zhu
W
W
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Brauchle
M A
MA
Di Padova
F
F
Gram
H
H
New
L
L
Ono
K
K
Downey
J S
JS
Han
J
J
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D005796:Genes / Q000187:drug effects* / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010766:Phosphorylation; D020871:RNA Stability / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases