Cellular mutants define a common mRNA degradation pathway targeting cytokine AU-rich elements.
To functionally classify AU-rich elements (AREs) from six different cytokine mRNAs, we made use of two previously described HT1080-derived cellular mutants (slowA, slowC) that lack a function required for the rapid degradation of interleukin-3 (IL-3) mRNA. Here we show that the defect is specific for ARE-containing mRNAs, whereas nonsense-mediated decay is intact. Degradation of beta-globin reporter transcripts mediated by the AREs of IL-3, GM-CSF, and TNFalpha, as well as by the structurally different and less potent AREs of IL-2 and IL-6, is impaired in both mutants. All these reporter transcripts are also sensitive to decay induced by ectopic expression of the RNA-binding protein tristetraprolin in the slowC background. Thus, we concluded that the mutants slowA and slowC define a common mRNA degradation pathway that targets cytokine AREs. In NIH3T3 cells, this decay pathway becomes incapacitated by upstream signaling from p38 MAP- or PI3-kinases, which independently stabilize cytokine ARE-containing transcripts. In contrast, c-fos ARE-directed mRNA degradation proceeds through a different pathway not affected by these kinases.
Stoecklin
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G
Institute of Medical Microbiology, University of Basel, Switzerland.
Stoeckle
P
P
Lu
M
M
Muehlemann
O
O
Moroni
C
C
D020413:3' Untranslated Regions / Q000378:metabolism; D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D018389:Codon, Nonsense; D016207:Cytokines / Q000235:genetics*; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics; D007377:Interleukin-3 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012313:RNA; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D020218:Response Elements; D051816:Tristetraprolin; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016335:Zinc Fingers; D048051:p38 Mitogen-Activated Protein Kinases
D020413:3' Untranslated Regions; D018389:Codon, Nonsense; D016207:Cytokines; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007376:Interleukin-2; D007377:Interleukin-3; D015850:Interleukin-6; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; C497553:Zfp36 protein, mouse; D015847:Interleukin-4; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases