RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence

Galloway, Alison; Saveliev, Alexander; Lukasiak, Sebastian; Hodson, Daniel J.; Bolland, Daniel J.; Balmanno, Kathryn; Ahlfors, Helena; Monzón-Casanova, Elisa; Mannurita, Sara Ciullini; Bell, Lewis S.; Andrews, Simon; Díaz-Muñoz, Manuel D.; Cook, Simon J.; Corcoran, Anne E.; Turner, Martin

doi:10.1126/science.aad5978

Cited by 152 publications

(150 citation statements)

References 51 publications

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“…Interestingly, in the same system the expression of GFP–TTP-AA was strongly anti-proliferative and reduced the viability of cells to 50% after 20h of doxycycline treatment (Figure 6B). This suggested a potential role for TTP in cell cycle regulation as proposed for the other two Zfp36 family members Zfp36l1 and Zfp36l2 (60). Analysis of apoptosis by 7-amino-actinomycin D (7-AAD) incorporation showed that induction of GFP–TTP-AA expression with doxycycline increased the number of apoptotic cells over time, whereas expression of GFP and GFP–TTP had no effect (Figure 6C).…”

Section: Resultsmentioning

confidence: 67%

The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation

et al. 2016

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RNA-binding proteins (RBPs) facilitate post-transcriptional control of eukaryotic gene expression at multiple levels. The RBP tristetraprolin (TTP/Zfp36) is a signal-induced phosphorylated anti-inflammatory protein guiding unstable mRNAs of pro-inflammatory proteins for degradation and preventing translation. Using iCLIP, we have identified numerous mRNA targets bound by wild-type TTP and by a non-MK2-phosphorylatable TTP mutant (TTP-AA) in 1 h LPS-stimulated macrophages and correlated their interaction with TTP to changes at the level of mRNA abundance and translation in a transcriptome-wide manner. The close similarity of the transcriptomes of TTP-deficient and TTP-expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2, whereas retained RNA-binding capacity of TTP-AA to 3′UTRs caused profound changes in the transcriptome and translatome, altered NF-κB-activation and induced cell death. Increased TTP binding to the 3′UTR of feedback inhibitor mRNAs, such as Ier3, Dusp1 or Tnfaip3, in the absence of MK2-dependent TTP neutralization resulted in a strong reduction of their protein synthesis contributing to the deregulation of the NF-κB-signaling pathway. Taken together, our study uncovers a role of TTP as a suppressor of feedback inhibitors of inflammation and highlights the importance of fine-tuned TTP activity-regulation by MK2 in order to control the pro-inflammatory response.

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Section: Resultsmentioning

confidence: 67%

The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation

et al. 2016

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“…Additional reporter gene assays indicate that ZFP36L1-dependent regulation requires a region containing conserved AU-rich elements in the 3′-UTR of Cyp7a1 mRNA. Indeed, previous studies have shown that Zfp36l1 functions to repress cytokine and cell-cycle mRNAs by binding to AU-rich sequences in their 3'-UTRs (13,27,31). However, a role for Zfp36l1 in regulating hepatic mRNAs in vivo, including those involved in lipid and bile acid metabolism, has not been reported.…”

Section: Discussionmentioning

confidence: 96%

RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism

Tarling¹,

Clifford²,

Cheng³

et al. 2017

Journal of Clinical Investigation

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“…Although at their inception CLIP techniques did not attend to background (Ule et al 2003(Ule et al , 2005Hafner et al 2010;Konig et al 2010), it has since been shown that significant background remains in CLIP experiments (Friedersdorf and Keene 2014) and that accounting for it greatly improves identification of binding sites ReyesHerrera et al 2015;Conway et al 2016;Galloway et al 2016;Holmqvist et al 2016;Van Nostrand et al 2016). However, it is not known whether this is due to improved signal-to-noise detection or whether the difference in enrichment represents quantitative differences in binding to various submotifs (Kishore et al 2011;Lambert et al 2015;Conway et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Quantifying RNA binding sites transcriptome-wide using DO-RIP-seq

Nicholson

Friedersdorf

Keene

2016

RNA

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RNA-binding proteins (RBPs) and noncoding RNAs orchestrate post-transcriptional processes through the recognition of specific sites on targeted transcripts. Thus, understanding the connection between binding to specific sites and active regulation of the whole transcript is essential. Many immunoprecipitation techniques have been developed that identify either whole transcripts or binding sites of RBPs on each transcript using cell lysates. However, none of these methods simultaneously measures the strength of each binding site and quantifies binding to whole transcripts. In this study, we compare current procedures and present digestion optimized (DO)-RIP-seq, a simple method that locates and quantifies RBP binding sites using a continuous metric. We have used the RBP HuR/ELAVL1 to demonstrate that DO-RIP-seq can quantify HuR binding sites with high coverage across the entire human transcriptome, thereby generating metrics of relative RNA binding strength. We demonstrate that this quantitative enrichment of binding sites is proportional to the relative in vitro binding strength for these sites. In addition, we used DO-RIP-seq to quantify and compare HuR's binding to whole transcripts, thus allowing for seamless integration of binding site data with whole-transcript measurements. Finally, we demonstrate that DO-RIP-seq is useful for identifying functional mRNA target sets and binding sites where combinatorial interactions between HuR and AGOmicroRNAs regulate the fate of the transcripts. Our data indicate that DO-RIP-seq will be useful for quantifying RBP binding events that regulate dynamic biological processes.

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RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence

Cited by 152 publications

References 51 publications

The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation

The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation

RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism

Quantifying RNA binding sites transcriptome-wide using DO-RIP-seq

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