Tristetraprolin Down-Regulates <i>IL-2</i> Gene Expression through AU-Rich Element-Mediated mRNA Decay

Ogilvie, Rachel L.; Abelson, Michelle; Hau, Heidi H.; Vlasova, Irina A.; Blackshear, Perry J.; Bohjanen, Paul R.

doi:10.4049/jimmunol.174.2.953

Cited by 187 publications

(182 citation statements)

References 49 publications

(42 reference statements)

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“…A number of specific ARE-containing mRNAs, including other chemokines, have been demonstrated to exhibit sensitivity to TTP (29,30,54,55). A recent study using oligonucleotide microarray analysis examined a broader spectrum of transcripts for TTP sensitivity in embryonic fibroblasts from wild-type and TTP Ϫ/Ϫ mice and identified a relatively small subset of sensitive mRNAs (31).…”

Section: Discussionmentioning

confidence: 99%

Tristetraprolin Regulates CXCL1 (KC) mRNA Stability

Datta

Biswas

Novotny

et al. 2008

The Journal of Immunology

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mRNAs encoding proinflammatory chemokines are regulated posttranscriptionally via adenine-uridine-rich sequences (AREs) located in the 3′ untranslated region of the message, which are recognized by sequence-specific RNA-binding proteins. One ARE binding protein, tristetraprolin (TTP), has been implicated in regulating the stability of several ARE-containing mRNAs, including those encoding TNF-α and GM-CSF. In the present report we examined the role of TTP in regulating the decay of the mouse chemokine KC (CXCL1) mRNA. Using tetR-regulated control of transcription in TTP-deficient HEK293 cells, KC mRNA half-life was markedly decreased in the presence of TTP. Deletion and site-specific mutagenesis were used to identify multiple AUUUA sequence determinants responsible for TTP sensitivity. Although a number of studies suggest that the destabilizing activity of TTP is subject to modulation in response to ligands of Toll/IL-1 family receptors, decay mediated by TTP in 293 cells was not sensitive to stimulation with IL-1α. Using primary macrophages from wild-type and TTP-deficient mice, KC mRNA instability was found to be highly dependent on TTP. Furthermore, LPS-mediated stabilization of KC mRNA is blocked by inhibition of the p38 MAPK in macrophages from wild-type but not TTP-deficient mice. These findings demonstrate that TTP is the predominant regulator of KC mRNA decay in mononuclear phagocytes acting via multiple 3′-untranslated region-localized AREs. Nevertheless, KC mRNA remains highly unstable in cells that do not express TTP, suggesting that additional determinants of instability and stimulus sensitivity may operate in cell populations where TTP is not expressed.

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Section: Discussionmentioning

confidence: 99%

Tristetraprolin Regulates CXCL1 (KC) mRNA Stability

Datta

Biswas

Novotny

et al. 2008

The Journal of Immunology

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“…Many other mediators of immunity or inflammation are encoded by labile mRNAs that also have adenylate/uridylate-rich elements (AREs) in their 3' UTRs. COX-2, CSF2 and IL-2 genes are dysregulated in the absence of TTP (Carballo et al, 2000;Ogilvie et al, 2005;Phillips et al, 2004), and it seems likely that expression of other inflammatory mediators will also prove to be controlled by TTP. Inflammatory mRNAs can be stabilized via the phosphorylation and inactivation of TTP by MAPK-activated protein kinase 2, a kinase that is activated by p38 MAPK (Carballo et al, 2001;Chrestensen et al, 2004;Stoecklin et al, 2004).…”

Section: Tristetraprolinmentioning

confidence: 99%

Anti-inflammatory functions of glucocorticoid-induced genes

Clark

2007

Molecular and Cellular Endocrinology

237

193

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“…A similar approach was used to demonstrate that GM-CSF mRNA is a physiological target of TTP; this study also provided evidence for an effect of TTP on mRNA deadenylation (Carballo et al, 2000). Other TTP targets, such as IL-2 (Ogilvie et al, 2005)and Ier3 (Lai et al, 2006) mRNAs, have been validated as endogenous targets using TTP-knockout fibroblasts or lymphocytes after Act D treatment.…”

Section: Systems For Studying Tzf Protein-mediated Mrna Decaymentioning

confidence: 99%

“…The optimal binding site recognized by TTP and its relatives is the UUAUUUAUU nonamer Brewer et al, 2006;Brewer et al, 2004;Hall, 2005;Hudson et al, 2004;Lai and Blackshear, 2001;Lai et al, 1999;Lai et al, 2005;Worthington et al, 2002), which is present in tandem and often overlapping repeats in TNFα, GM-CSF, and IL-2 mRNAs, each confirmed physiological targets of TTP (Carballo et al, 1998;Carballo et al, 2000;Ogilvie et al, 2005). TTP binds to and subsequently destabilizes target mRNAs by an incompletely understood mechanism that most likely involves the recruitment or activation of poly-A ribonuclease (PARN), an enzyme with 3'-5' poly(A) tail exonuclease activity .…”

Section: Introductionmentioning

confidence: 99%

“…TTP deficiency is associated with tumor necrosis factor-alpha (TNFα) overexpression (Blackshear, 2002;Carballo et al, 1998;Lai et al, 1998), and TTP has been shown to promote deadenylation and destruction of TNFα mRNA (Carballo et al, 1998;Lai et al, 1999). TTP may regulate overlapping aspects of immune cell function, inflammation and autoimmunity by targeting, in addition to TNFα, other essential mRNAs (Carballo et al, 1998;Carballo et al, 2000;Lai et al, 2006;Ogilvie et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Evaluating the Control of mRNA Decay in Fission Yeast

Cuthbertson

Blackshear

2008

Methods in Enzymology

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Abnormalities in rates of mRNA decay can lead to changes in normal, steady-state levels of transcripts, which in turn can result in changes in protein production and abnormal phenotypes. For example, mice deficient in the gene encoding tristetraprolin (TTP), a tandem CCCH zinc finger domain protein, develop a complex syndrome that includes wasting, arthritis, and myeloid hyperplasia, all secondary to elevated levels of tumor necrosis factor alpha (TNF). This in turn reflects elevated levels of TNF mRNA, which is a direct "target" of TTP binding and TTPpromoted deadenylation and decay. Three TTP-like proteins are expressed in man, and four in mice, all of which share functional homologies of mRNA binding ability and control of transcript decay. In contrast, the Schizosaccharomyes pombe genome contains only one TTP-like protein, named zfs1. Microarray analysis revealed that S. pombe cells deficient in zfs1 overexpress the arz1 mRNA, which has several ideal TTP-like binding sites in its 3'-untranslated region (UTR). We used the "no message in thiamine (nmt)" repressible system, in which thiamine rapidly shuts off gene transcription, to evaluate the relative stability of the arz1 mRNA in wild-type and zfs1-deficient cells. We found that the arz1 mRNA decayed much more rapidly in the presence of endogenous zfs1 than in its absence. The nmt system also proved useful for the study of mRNA sequence elements that are essential for interactions with zfs1, which eventually results in accelerated transcript decay. These studies illustrates the utility of the S. pombe nmt system for evaluating protein-mRNA interactions that affect mRNA decay in vivo, and provide an alternative to the use of transcription inhibitors or heat-sensitive polymerase promoters that are more commonly used to evaluate mRNA decay in Saccharomyces cerevesiae. We hope to use this convenient experimental system to unravel the mechanism by which TTP family members, in this and other organisms, bind to mRNAs and promote their instability.

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Tristetraprolin Down-Regulates IL-2 Gene Expression through AU-Rich Element-Mediated mRNA Decay

Cited by 187 publications

References 49 publications

Tristetraprolin Regulates CXCL1 (KC) mRNA Stability

Tristetraprolin Regulates CXCL1 (KC) mRNA Stability

Anti-inflammatory functions of glucocorticoid-induced genes

Evaluating the Control of mRNA Decay in Fission Yeast

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