Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tristetraprolin (ZFP36) and TIS11B (ZFP36-L1)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101947

Synonyms

Historical Background

The characterization of the tristetraprolin (TTP) family of RNA-binding proteins started in the early 1990s when Harvey Herschmann first cloned an immediate-early response gene induced by the carcinogenic phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) that he named TIS-11, standing for TPA-induced sequence 11 (Varnum et al. 1989). This and concurrent teams rapidly established that the cellular expression of this mRNA displayed an almost undetectable level under the quiescent state but rapid and transient induction under stimulation by serum and various growth factors or hormones. cDNA cloning of other family members based on sequence similarity of repeated YKTELC sequences revealed a family of three proteins, named TIS11, TIS11b, and TIS11d, that shared also two cysteine-histidine repeats. The term tristetraprolin was coined by Perry Blackshear when the analysis of the protein sequence of a TIS11 homolog identified as an insulin-response gene in mouse 3 T3-L1 cells revealed the presence of three PPPP (tetraprolin) repeats (Lai et al. 1990). The conserved interspersed C-C-C-H sequences present in TTP and its orthologs were quite rapidly demonstrated to be zinc-finger domains, but, given that TTP subcellular localization appeared nuclear in several unstimulated cell types, it was first proposed that it might be a DNA-binding protein with a transcription factor activity. It took more than a decade to discover that TTP and its homologs bind RNA rather than DNA. The generation of TTP-null mice by the Blackshear laboratory in 1996 represented a first significant step since these mice were viable but developed marked symptoms since 8 weeks after birth including medullary and extramedullary myeloid hyperplasia, arthritis, dermatitis, weight loss, and cachexia (Taylor et al. 1996). Almost all these symptoms could be corrected by the injection of anti-TNFα antibodies, identifying this cytokine as a major target of TTP action (Taylor et al. 1996). In 1998, the same laboratory published a seminal paper reporting for the first time that TTP binds the AU-rich elements (AREs) located in the 3′-untranslated region (3′-UTR) of the TNFα mRNA and thereby accelerates its degradation (Carballo et al. 1998). They could show that the GM-CSF and IL3 mRNAs are also regulated through the same mechanisms. From then, the number of studies aimed at identifying target mRNAs of the TTP family members increased exponentially. The genetic invalidations of the related members TIS11b and TIS11d in mice were reported in 2004 and interestingly revealed distinct phenotypes from that of the TTP knockout mouse, suggesting that these functionally similar proteins are not redundant in vivo. Several studies have then tried to exploit the biological properties of these RNA-destabilizing proteins in order to treat specific pathologies including inflammatory diseases and cancer.

Structure

In humans, the ZFP36 gene is located on chromosome 19q13.1 whereas the ZFP36-L1 gene (encoding TIS11b) is located on chromosome 14q24.1. Both genes are composed of two exons and one intron. Analyses of the 5′-proximal region of ZFP36 gene revealed the presence of various promoter elements and consensus binding sites for transcription factors such as SP1, EGR-1, AP2, or Smad3/Smad4 that mediate the transcriptional response to serum and growth factors (Sanduja et al. 2012). The promoter of ZFP36-L1 has been less studied but, interestingly, a recent study identified a cAMP response element that mediates the specific induction of this family member (in contrast to ZFP36 and ZFP36-L2) by ACTH in adrenocortical cells (Rataj et al. 2016).

A surprising characteristic of ZFP36 and ZFP36-L1 mRNAs is that they possess several AU-rich elements in their own 3′-UTR that may contribute to self-regulation through mRNA decay mechanisms. Accordingly, the half-lives of these two mRNAs are relatively short (less than 60 minutes in various cell types) and the induction of their expression by growth factors or hormones is usually transient, the transcriptional effects being rapidly turned down by rapid subsequent mRNA degradation.

The proteins TTP and TIS11b are 326 and 338 amino acid-long, respectively. Their overall structure is presented in Fig. 1. Both proteins present a similar structure centered on two zinc-fingers that are essential to their mRNA-binding activity (RNA-binding domain, RBD). Both zinc fingers are preceded by a conserved R/KYKTEL sequence whose function is still unknown. The two zinc fingers have the same CX8CX5CX3H sequence and are separated by a conserved 12 amino-acid long spacer that contains a nuclear localization sequence. TTP and TIS11b each contain two domains, the N-terminal domain (NTD) and the C-terminal domain (CTD) that can activate mRNA decay. Both domains bind to components of the mRNA decay machinery to trigger mRNA degradation. Although they were used to name TTP, the three tetraprolin (PPPP) motifs are not conserved in TIS11b and the use of the names ZFP36 (zinc finger protein of 36 kDa) and ZFP36-L1 (ZFP36-like1) thus appears more appropriate. A number of phosphorylation sites have been identified by phosphoproteomics, but for only few of them the responsible kinase been identified. The phosphorylation sites of the human proteins that have been confirmed in vitro and in cellula are shown on Fig. 1. Serine residue 186 of TTP (homologous to S178 in the original publication using the mouse sequence) is substrate of the mitogen-activated protein kinase-activating protein kinase 2 (MK2) (Baou et al. 2009; Sanduja et al. 2012; Ciais et al. 2013). Serine 186 is conserved in TIS11b (S203) and has been shown to be a substrate for MK2 and protein kinase B in vitro and in cellula (Baou et al. 2009; Sanduja et al. 2012; Ciais et al. 2013). Since the amino-acids surrounding the phosphorylated serine are well conserved, one can suppose that MK2 and PKB can phosphorylate both TTP and TIS11b at this similar site. In addition, MK2 phosphorylates an additional serine (S60, homologous to S52 in the original publication using the mouse sequence) in TTP and PKB phosphorylate two additional serines (S54 and S92) in TIS11b (Baou et al. 2009; Planel et al. 2014). These residues are not conserved in the other member of the family. More recently, cAMP-dependent protein kinase (PKA) was reported to phosphorylate two serine residues in TIS11b (S54 and S334) (Rataj et al. 2016). Although S54 was already reported to be a substrate for PKB, S334 appears as new site which, in contrast to S54, is conserved in TTP. The biological effects of the phosphorylations on these different sites will be discussed thereafter.
Tristetraprolin (ZFP36) and TIS11B (ZFP36-L1), Fig. 1

Structure and phosphorylation sites of TTP and TIS11b. The upper panel depicts the structural organization of TTP and TIS11b mRNAs. Tje AU-rich elements present in the 3′-untranslated regions of both mRNAs are indicated by red boxes. The lower panel shows the structures and phosphorylation sites of TTP and TIS11b. The double zinc fingers are represented by red boxes, the tetraprolin sites by light green boxes (only a degenerated triprolin residue is present in TIS11b), the nuclear localization sequences (NLS) by dark green boxes, and the nuclear export sequences (NES) by orange boxes. The phosphorylation sites (S: serine residues) are represented by purple circles and the acronyms of the kinases that phosphorylate the corresponding sites are indicated into brackets. The putative phosphorylations that can be deduced from protein sequence homologies but have not been demonstrated in vivo yet are written in grey. The lower part of the figure defines the N-terminal domains (NTD), RNA-binding domain (RBD), and C-terminal domain of each protein

Target Genes and Functions

Once the Blackshear laboratory has established that the zinc fingers of TTP bind with high selectivity to the AU-rich elements (AREs) located in the 3′-UTR of TNFα mRNA, an increasing number of research groups started to study the binding of TTP or TIS11b to other ARE-rich mRNA 3′-UTRs. Many target mRNAs have thus been identified in vitro and in cellula. They are listed in some recent reviews (Baou et al. 2009; Sanduja et al. 2011; Planel et al. 2014). They encode several growth factors, angiogenesis regulators, inflammatory cytokines, and cell cycle regulators which share the property of being rapidly turned on or turned off under various stress conditions. Identification and analysis of the RNA sequences selectively bound by TTP in RNA SELEX experiments confirmed the preferential recognition of the core AUUUA element but showed also strong specificity for the extended UAUUUAU motif. However, as reviewed in (Ciais et al. 2013), TTP family members can also bind non-ARE sequences including the CTTGTG motif.

The pioneering publications of the Blackshear laboratory indicated that TTP-dependent destabilization of ARE-rich target mRNAs requires deadenylation by the deadenylase PARN through an indirect mechanism that does not involve a direct binding of PARN to TTP. Further reports indicated that TTP and TIS11b recruit several mRNA decay enzymes onto AREs, including the large cytoplasmic deadenylation complex CCR4-CAF-NOT1. TTP also favors deadenylation through binding to PABP (poly(A)-binding protein) thereby suppressing its protective action against mRNA degradation. Once the poly(A) tail has been removed, mRNA degradation occurs both in a 3′ to 5′ and in a 5′ to 3′ direction. On the 3′-end, TTP proteins interact with the exosome, a multiproteic ribonuclease complex which associates itself with the scavenger decapping enzyme DcpS to achieve 3′-degradation of the transcript. On the 5′-end, TTP proteins interact with the decapping enzymes Dcp1 and Dcp2 and promote 5′-degradation of the transcript via the cytoplasmic 5′-3′ exonuclease Xrn1. Taken together, these observations suggest that, once TTP or TIS11b have bound the ARE domains of their target mRNAs, they act as docking platforms for the recruitment of a whole machinery of decapping enzymes and degrading exonucleases that mediate rapid mRNA degradation from both its 3′- and 5′-ends (Baou et al. 2009; Sanduja et al. 2012; Ciais et al. 2013). Pathways and major components of ARE-mediated mRNA decay through the action of TTP or TIS11b are illustrated in Fig. 2.
Tristetraprolin (ZFP36) and TIS11B (ZFP36-L1), Fig. 2

Function of TTP and TIS11b in ARE-mediated mRNA decay. TTP and TIS11b bind to AU-rich elements in the 3′-UTR of target mRNAs and recruit the deadenylase complex directly (CCR4-CAF-NOT1 complex) or indirectly (PARN) to trigger mRNA deadenylation. Deadenylated transcripts are degraded through TTP- or TIS11b-mediated recruitment of the exosome, a multiprotein complex that promotes the 3′ to 5′ mRNA decay. Alternatively, deadenylation can be followed by mRNA decapping by the decapping enzymes Dcp1/Dcp2 and the 5′ to 3′ mRNA degradation by the Xrn1 exonuclease

A number of other TTP and TIS11b functions that affect mRNA biogenesis and degradation are reviewed in (Ciais et al. 2013). They comprise control of alternative polyadenylation sites, control of mRNA subcellular localization (nuclear export, accumulation in processing bodies, shuttling between processing bodies and stress granules), and repression of translation.

Gene Invalidation in Mice

As mentioned before, the generation of the TTP knockout mice was determinant in the understanding of the function of this protein. As shown in Table 1, the phenotype of the TTP−/− mice revealed a massive inflammatory syndrome leading to rapid postnatal death (Taylor et al. 1996). This syndrome could be corrected by injection of anti-TNFα antibodies (Taylor et al. 1996), pointing out that this cytokine is a physiological target of TTP. Evidence that macrophage progenitors were responsible for the overproduction of TNFα in these mice came from a latter study showing that transplantation of TTP-KO bone marrow into immunodeficient Rag2−/− mice reproduced the inflammatory phenotype, although with a lag of nearly 6 months. The phenotype of TIS11b−/− mice appeared quite different from that of TTP-KO mice. Two independent studies reported that the TIS11b-KO mice died in utero at E10.5/E11 from severe placental defects (Stumpo et al. 2004; Bell et al. 2006). One study pointed out VEGF as a determinant target gene whose expression was deregulated in KO embryos and might explain the vasculogenesis and angiogenesis defects causing abnormal placental development (Bell et al. 2006). The VEGF mRNA had been previously shown to possess several AU-rich elements in its 3′-UTR and two of them had been shown to bind TIS11b, leading to VEGF mRNA decay (Ciais et al. 2004). However, in embryonic fibroblasts from TIS11b-KO mice, VEGF appeared to be upregulated at the translational level rather than at the level of mRNA stability (Bell et al. 2006). It is interesting to remark that, whereas in vitro TTP, TIS11b, and TIS11d are all able to bind the VEGF mRNA 3′-UTR and to destabilize VEGF mRNA (Ciais et al. 2004), in vivo it appears to be a specific target of TIS11b. The specificity of in vivo action of the TTP family members thus appears to rely mostly on their distinct sites of expression and modes of regulation.
Tristetraprolin (ZFP36) and TIS11B (ZFP36-L1), Table 1

Phenotypes of the TTP and TIS11b knockout mice

Gene

Type of knockout

Phenotype

Ref.

ZFP36 (TTP)

Neomycin resistance gene inserted into the second exon of the coding sequence (generating stop codons upstream of the zinc fingers)

−/− mice are normal at birth

Between 1–8 weeks after birth: Failure of weight gain, cachexia, alopecia, dermatitis, arthritis, conjunctivitis, myeloid hyperplasia

The phenotype is corrected by injection of anti-TNFα antibodies

The phenotype is reproduced by transplantation of −/− bone marrow into wild type immunodeficient mice

Taylor et al. 1996

ZFP36-L1 (TIS11b)

Neomycin resistance gene inserted into the second exon of the coding sequence (generating stop codons upstream of the zinc fingers)

−/− mice die in utero at E11

Failure of chorioallantoic fusion

Neural tube abnormalities

Stumpo et al. 2004

ZFP36-L1 (TIS11b)

Neomycin resistance gene inserted into the second exon of the coding sequence (generating stop codons upstream of the zinc fingers)

−/− mice die in utero at E10.5

Neural tube and placental defects associated with defects in vasculogenesis and angiogenesis

Increased VEGF-A expression in KO embryos

Increased VEGF-A translation in KO murine embryonic fibroblasts

Bell et al. 2006

Regulation of TTP and TIS11b Activity (Transcription, Phosphorylation, Intracellular Shuttling)

Since they control rapid changes in their target mRNA levels, the expression levels and activities of TTP and TIS11b are themselves tightly regulated by extracellular signals (growth factors, hormones, inflammatory cytokines, hypoxia). These regulations occur at several different levels including transcription, phosphorylation, protein stability, and subcellular localization.

Since the early descriptions of TTP and TIS11b, it was immediately noticed that their expressions are very rapidly (within 30 min) induced by a variety of external stimuli such as growth factors and phorbol esters and that they could be considered by several means as immediate-early genes. The list of transcriptional inducers of TTP and/or TIS11b expression has since enlarged and now comprises hormones such as insulin or ACTH, inflammatory products such as LPS, and environmental conditions such as hypoxia or hypertonicity. Although there is great variability between cell types and between inducing signaling pathways, it appears that induction of TTP is in many situations more transient than induction of TIS11b, suggesting that TTP mRNA is more rapidly and efficiently downregulated via the feedback destabilization of its ARE-rich 3′-UTR. The different patterns of inductions are described in recent reviews (Baou et al. 2009; Sanduja et al. 2011).

As presented in the previous chapter, TTP and TIS11b are phosphorylated by a variety of protein-kinases. The impact of these phosphorylations on mRNA-destabilizing activity is still a matter of debate, with some studies indicating that the dephospho-forms of TTP have a stronger affinity for ARE-rich mRNAs than the phospho-forms and other studies reporting that phosphorylation by ERK, p38 MAP-Kinase/MK2, or JNK kinase does not impact this affinity. Similarly, phosphorylation of TIS11b by PKB/Akt or MK2 did not affect its ability to bind AREs but nevertheless inhibited its ability to promote ARE-mRNA degradation. One part of the explanation is that phosphorylation of TTP and TIS11b at conserved serine residues (S52 and S178 in mouse TTP; S92 and S203 in human TIS11b) enhances their interaction with 14.3.3 proteins and thereby protects them from proteasomal degradation. The current accepted model thus states that, upon signaling protein-kinase activation (MK2, PKB), phosphorylation of TTP and TIS11b occurs and favors their sequestration by 14.3.3 proteins and thereby reduces their overall mRNA destabilizing action. Dissipation of the signal implies dephosphorylation of phospho-TTP and phospho-TIS11b, probably via protein phosphatase PP2A. A new phosphorylation site recently identified in TIS11b seems however to mediate a different biological response. The cAMP-dependent protein-kinase (PKA) was reported to induce the phosphorylation of TIS11b on two serine residues, S54 and S334 (Rataj et al. 2016). Analysis of phospho-dead (S54A, S334A) and phosphomimick (S54D, S334D) TIS11b mutants revealed that S54 regulates the binding of TIS11b to 14.3.3 protein but that S334 does not play a significant role in this interaction. In contrast, the C-terminal S334 phosphosite appears to be involved in the interaction with the CCR4-NOT1 deadenylation complex. TIS11b S334D phosphomimick mutants presented a reduced association with CNOT1, a core subunit of the CCR4-NOT complex (Rataj et al. 2016), thus confirming recent structural studies characterizing a multiprotein complex between the C-terminal domain of TTP and CCR4-NOT (Fabian et al. 2013). These studies highlighted the importance of S323 in TTP, which corresponds to S334 in TIS11b, for its interaction with the CCR4-NOT complex. Unexpectedly, TIS11b S334D phosphomimick mutant displayed an increased mRNA-destabilizing activity as compared to wild type TIS11b, which appeared to be mediated by an enhanced association of TIS11b S334D with the decapping enzyme Dcp1a (Rataj et al. 2016). These observations suggest that combinatorial phosphorylations of TTP or TIS11b on specific residues do not systematically abrogate their mRNA destabilizing capability but rather fine-tune their interactions with the mRNA decay machineries.

TTP and TIS11b are nucleocytoplasmic shuttling proteins. Both proteins contain a specific nuclear localization sequence (NLS) located between the two zinc fingers. Murine TTP has a nuclear export signal (NES) between amino acids 1–15 while murine TIS11b NES has been mapped between amino acids 305–313. Subcellular localization studies that the nuclear or cytoplasmic localizations of TTP and TIS11b differ from one cell type to another and are regulated by signaling pathways. Nuclear export depends on the nuclear export receptor CRM1 since inhibition of CRM1 resulted in nuclear accumulation of TTP. In general, TTP and TIS11b are expressed at low levels in the nucleus and cytoplasm of unstimulated cells and are almost exclusively expressed in the cytoplasm of stimulated cells. Nuclear to cytoplasmic shuttling of TTP has been shown to be regulated through phosphorylation at Ser52 and Ser178 by the p38 MAPK pathway whereas hypophosphorylated forms of TTP were found to be nuclear. It was then proposed that upon inflammation-mediated activation of p38 signaling pathway, expressions of both TNFα mRNA, the major target of TTP and TTP protein are increased and coupled to TTP phosphorylations. TTP phosphorylation on Ser52 and Ser178 stabilizes TTP protein in the cytoplasm and prevents its mRNA-destabilizing function, thus favoring TNFα mRNA stabilization and translation. During inflammation resolution, TTP is dephosphorylated and activated, leading to TNFα mRNA destabilization. TTP could progressively relocalize to the nucleus and/or be degraded by the proteasome. Nevertheless, TTP was shown to remain nuclear in Balb/C 3 T3 cells after stimulation with serum. In human umbilical vein endothelial cells (HUVEC), TTP is cytoplasmic in resting cells and becomes nuclear after stimulation with TNF-α. In resting human umbilical aortic endothelial cells (HUAEC), TIS11b is mostly located in the nucleus and ensures a novel function in mRNA 3′-end processing (Ciais et al. 2013). More recently, determination of TTP binding site atlas in macrophages stimulated with LPS revealed that 64% of TTP binding sites were located within introns of its target genes while 35% were found in target gene 3′-UTRs (Sedlyarov et al. 2016). The role of TTP binding to introns remains elusive because no function of TTP in pre-mRNA processing has been detected. Rather TTP was found to be associated with spliced-out introns, suggesting its potential role in the outcome of intronic RNA. These data however suggest that the function of TTP or TIS11b might depend on their nucleocytoplasmic localization.

In the cytoplasm, TTP and TIS11b can localize to processing bodies (PBs), which are cytoplasmic foci of mRNAs and enzymes that have been proposed as sites of mRNA decay and translational silencing. TTP and TIS11b can deliver ARE-containing mRNA to PBs for decay and induce PB nucleation through aggregation of ribonucleoproteins. PBs contain decapping (Dcp1a and Dcp2) and 5′ to 3′ decay enzymes (Xrn1) as well as deadenylases. On the other hand, under conditions of cellular stress, TTP and TIS11b can be recruited to stress granules (SGs) where they have been shown to target ARE-containing transcripts. Stress granules are also small cytoplasmic foci that contain translationally arrested mRNAs, stalled translation initiators factors, and the ARE-binding proteins TIA-1 and TIAR. Dynamic contacts have been observed between PBs and SGs and it was suggested that TTP may control trafficking of ARE-containing transcripts between PBs and SGs, thus directing them toward translational repression or degradation.

TTP and TIS11b in Inflammatory Diseases and Cancer

The involvement of TTP in inflammatory disorders was the first finding linking TTP protein family to diseases. As aforementioned, TTP KO mice displayed an inflammatory syndrome due to TNFα overproduction, which was almost abrogated by injection of anti-TNFα antibodies (Taylor et al. 1996). Another target of TPP in vivo is GM-CSF of which overexpression contributes to myeloid hyperplasia in TTP KO mice. Examination of patients with inflammatory diseases such as rheumatoid arthritis (RA) revealed an inverse relationship between TTP expression in synovium and the degree of inflammation. However, TTP expression in normal synovium has not been examined. In searching for molecular mechanisms that could explain TTP underexpression in RA, Carrick et al. identified a single nucleotide polymorphism (SNP) (C to T transition in exon 2) which was significantly associated with a higher incidence of RA in African-Americans subjects (Carrick et al. 2006). This SNP is predicted to slow TTP translation and consequently to favor inflammatory cytokine production. Another SNP has been identified in TTP promoter region (359A to G) and was involved in decreased TTP promoter activity. RA patients carrying this SNP tended to have an early onset of RA compared to those with the A allele. These finding suggest that genetic polymorphisms in TTP gene may impact TTP expression and may represent potential markers for susceptibility to inflammatory diseases. More recently, the essential role of TTP in the control of inflammation was confirmed by Patial et al. who reported that increasing TTP mRNA stability through ARE suppression in TTP transcript is an effective therapy in preclinical models of inflammatory bone loss (Patial et al. 2016).

Overexpression of ARE-containing transcripts encoding factors promoting growth, inflammation, angiogenesis, and invasion has been observed in carcinogenesis (Sanduja et al. 2012). These aberrant expressions result from dysfunctional ARE-mediated posttranscriptional control, which seems to be mainly due to deregulations in RNA-binding proteins rather than to ARE mutations. Downregulation of TTP expression has been found in a variety of human malignancies including breast, colon, prostate, and lung cancers. In breast cancer, the loss of TTP is predictive of poor prognosis. The loss of TTP expression seems to be an early event during tumorigenesis. Nevertheless, the mechanisms leading to TTP suppression in cancer remain obscure. As mentioned for inflammatory disorders, SNPs in TTP gene may account for TTP decreased expression. Indeed, a synonymous polymorphism (309C > T) has been identified in TTP in breast cancer patients (Griseri et al. 2011). This genetic polymorphism does not modify the corresponding amino acid but decreases TTP mRNA translation efficiency. Alternative reported mechanisms for TTP downregulation are microRNA-mediated silencing of TTP transcript and epigenetic modifications such as CpG island methylation in TTP promoter. Much less is known concerning TIS11b in cancer. A remarkable heterogeneity in TIS11b transcript expression levels has been observed in a panel of human cancer cell lines. These results will require validation by measurement of TIS11b protein levels.

The finding that re-expression of TTP in cancer cells leads to inhibition of cell proliferation and tumor growth through targeting of many mRNAs involved in angiogenesis, inflammation, and tumorigenesis, suggested that TTP might represent a novel tumor suppressor gene. This has led several research groups to take advantage of these properties to develop anticancer therapies. Stoecklin et al. overexpressed TTP in a v-H-Ras-dependent mast cell tumor model expressing an abnormally stable IL3 mRNA as part of an oncogenic autocrine loop (Sanduja et al. 2012; Planel et al. 2014). When TTP-expressing cells were transplanted in mice, tumor growth was delayed by 4 weeks and decreased IL3 mRNA levels were observed in TTP-expressing tumors. Implantation of Chinese hamster fibroblasts expressing Ras-Val12 oncogene and inducible TTP into nude mice resulted in a marked reduction of tumor growth, tumor VEGF levels, and tumor vascularization (Essafi-Benkhadir et al. 2007). Using a strategy based on the use of a cell-permeant variant of TIS11b injected into subcutaneous LLC (Lewis lung carcinoma) tumors, Planel et al. observed a significant decrease in the tumor growth rate, the tumor vascular density, and the tumor VEGF expression level (Planel et al. 2010). Very interestingly, not only VEGF but also FGF-1, EGF, IL1α, IL6, IL12, and TNFα protein levels were significantly decreased in permeant TIS11b-treated tumors. This work was first to establish that treatment of malignant tumors with an ARE-binding protein can be a novel multitarget therapy that simultaneously targets several important factors involved in angiogenesis and inflammation.

Summary

TTP (ZFP36) and TIS11b (ZFP36-L1) are two structurally related proteins characterized by a central domain containing two CCCH-type zinc fingers. These motifs are essential for binding to AU-rich sequences (AUUUA as a minimal sequence) located in the 3′-untranslated region (3′-UTR) of several target mRNAs. Although both proteins can regulate the same AU-rich 3′-UTRs in vitro, the genetic invalidation of each gene in mice has revealed very distinct phenotypes, indicating that their pattern of target mRNAs are distinct in vivo. As a consequence of binding AU-rich elements, TTP and TIS11b trigger the destabilization and subsequent degradation of target mRNAs through a complex mechanism that implies the recruitment of deadenylases (PARN, Pan2/Pan3/CCR4-NOT complex) and 3′- to 5′- ribonucleases (the exosome complex) as well as decapping enzymes (Dcp1/Dcp2) and 5′- to 3′- ribonucleases (Xrn1). The activity of these RNA-binding proteins is regulated at several distinct levels including subcellular localization (nucleocytoplasmic shuttling), phosphorylation (by MK2, PKB, PKA), transcription, and mRNA stability. Among the main targets of these proteins are the short-lived mRNAs encoding several cytokines and growth factors (TNFα, IL1α, IL6, VEGF). This has prompted several research teams to use the remarkable properties of these RNA-binding proteins to design innovative therapeutic strategies for the treatment of inflammatory diseases or cancer. Future developments will certainly proceed on this track of multitarget mRNA-destabilizing therapies.

See Also

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institut National de la Santé et de la Recherche Médicale Unité 1036GrenobleFrance
  2. 2.CEA, Biosciences and Biotechnology Institute of Grenoble, Laboratory Biology of Cancer and InfectionGrenobleFrance
  3. 3.University Grenoble-AlpesGrenobleFrance