The Experts below are selected from a list of 2172 Experts worldwide ranked by ideXlab platform
Perry J. Blackshear - One of the best experts on this subject based on the ideXlab platform.
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Tristetraprolin targets Nos2 expression in the colonic epithelium
Scientific reports, 2019Co-Authors: Melanie A. Eshelman, Perry J. Blackshear, Faoud T. Ishmael, Stephen M. Matthews, Emily M. Schleicher, Rebecca Fleeman, Yuka Imamura Kawasawa, Deborah J. Stumpo, Walter A. Koltun, Gregory S. YochumAbstract:Tristetraprolin (TTP), encoded by the Zfp36 gene, is a zinc-finger protein that regulates RNA stability primarily through association with 3' untranslated regions (3' UTRs) of target mRNAs. While TTP is expressed abundantly in the intestines, its function in intestinal epithelial cells (IECs) is unknown. Here we used a cre-lox system to remove Zfp36 in the mouse epithelium to uncover a role for TTP in IECs and to identify target genes in these cells. While TTP was largely dispensable for establishment and maintenance of the colonic epithelium, we found an expansion of the proliferative zone and an increase in goblet cell numbers in the colon crypts of Zfp36ΔIEC mice. Furthermore, through RNA-sequencing of transcripts isolated from the colons of Zfp36fl/fl and Zfp36ΔIEC mice, we found that expression of inducible nitric oxide synthase (iNos or Nos2) was elevated in TTP-knockout IECs. We demonstrate that TTP interacts with AU-rich elements in the Nos2 3' UTR and suppresses Nos2 expression. In comparison to control Zfp36fl/fl mice, Zfp36ΔIEC mice were less susceptible to dextran sodium sulfate (DSS)-induced acute colitis. Together, these results demonstrate that TTP in IECs targets Nos2 expression and aggravates acute colitis.
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Expression of the mRNA stability regulator Tristetraprolin is required for lactation maintenance in the mouse mammary gland.
Oncotarget, 2018Co-Authors: María Victoria Goddio, Perry J. Blackshear, Deborah J. Stumpo, Albana Gattelli, Johanna M. Tocci, Lourdes Pérez Cuervo, Micaela Stedile, Nancy E. Hynes, Roberto Meiss, Edith C. KordonAbstract:// Maria Victoria Goddio 1 , Albana Gattelli 1 , Johanna M. Tocci 1 , Lourdes Perez Cuervo 1 , Micaela Stedile 1 , Deborah J. Stumpo 3 , Nancy E. Hynes 2 , Perry J. Blackshear 3 , Roberto P. Meiss 4 and Edith C. Kordon 1 1 IFIBYNE-UBA-CONICET, Departamento de Quimica Biologica, FCEN-UBA, Buenos Aires, Argentina 2 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland 3 Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA 4 National Academy of Medicine, Buenos Aires, Argentina Correspondence to: Edith C. Kordon, email: ekordon@qb.fcen.uba.ar Keywords: lactation; Tristetraprolin; TNF alpha; cell death; mammary involution; Autophagy Received: July 10, 2017 Accepted: November 14, 2017 Published: January 03, 2018 ABSTRACT Tristetraprolin (TTP), an mRNA-binding protein that negatively controls levels of inflammatory factors, is highly expressed in the lactating mouse mammary gland. To determine the biological relevance of this expression profile, we developed bi-transgenic mice in which this protein is specifically down-regulated in the secretory mammary epithelium in the secretory mammary epithelium during lactation. Our data show that TTP conditional KO mice produced underweight litters, possibly due to massive mammary cell death induced during lactation without the requirement of additional stimuli. This effect was linked to overexpression of inflammatory cytokines, activation of STAT3 and down-regulation of AKT phosphorylation. Importantly, blocking TNFα activity in the lactating conditional TTP KO mice inhibited cell death and similar effects were observed when this treatment was applied to wild-type animals during 48 h after weaning. Therefore, our results demonstrate that during lactation TTP wards off early involution by preventing the increase of local inflammatory factors. In addition, our data reveal the relevance of locally secreted TNFα for triggering programmed cell death after weaning.
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Tristetraprolin expression by keratinocytes controls local and systemic inflammation
JCI insight, 2017Co-Authors: Mathieu Andrianne, Assiya Assabban, Denis A. Mogilenko, Delphine Staumont Salle, Sébastien Fleury, Gilles Doumont, Gaetan Van Simaeys, Sergei A. Nedospasov, Perry J. BlackshearAbstract:Tristetraprolin (TTP, encoded by the Zfp36 gene) regulates the mRNA stability of several important cytokines. Due to the critical role of this RNA-binding protein in the control of inflammation, TTP deficiency leads to the spontaneous development of a complex inflammatory syndrome. So far, this phenotype has been largely attributed to dysregulated production of TNF and IL‑23 by myeloid cells, such as macrophages or DCs. Here, we generated mice with conditional deletion of TTP in keratinocytes (Zfp36fl/flK14-Cre mice, referred to herein as Zfp36ΔEP mice). Unlike DC-restricted (CD11c-Cre) or myeloid cell-restricted (LysM-Cre) TTP ablation, these mice developed exacerbated inflammation in the imiquimod-induced psoriasis model. Furthermore, Zfp36ΔEP mice progressively developed a spontaneous pathology with systemic inflammation, psoriatic-like skin lesions, and dactylitis. Finally, we provide evidence that keratinocyte-derived TNF production drives these different pathological features. In summary, these findings expand current views on the initiation of psoriasis and related arthritis by revealing the keratinocyte-intrinsic role of TTP.
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An Ancient Family of RNA-Binding Proteins: Still Important!
Trends in Biochemical Sciences, 2017Co-Authors: Melissa L. Wells, Lalith Perera, Perry J. BlackshearAbstract:RNA-binding proteins are important modulators of mRNA stability, a crucial process that determines the ultimate cellular levels of mRNAs and their encoded proteins. The Tristetraprolin (TTP) family of RNA-binding proteins appeared early in the evolution of eukaryotes, and has persisted in modern eukaryotes. The domain structures and biochemical functions of family members from widely divergent lineages are remarkably similar, but their mRNA 'targets' can be very different, even in closely related species. Recent gene knockout studies in species as distantly related as plants, flies, yeasts, and mice have demonstrated crucial roles for these proteins in a wide variety of physiological processes. Inflammatory and hematopoietic phenotypes in mice have suggested potential therapeutic approaches for analogous human disorders.
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Tristetraprolin as a Therapeutic Target in Inflammatory Disease
Trends in pharmacological sciences, 2016Co-Authors: Sonika Patial, Perry J. BlackshearAbstract:Members of the Tristetraprolin (TTP) family of RNA-binding proteins are found in all major eukaryotic groups. TTP family members, from plants through humans, can bind adenosine-uridine rich elements in target mRNAs with high affinity. In mammalian cells, these proteins then promote deadenylation and decay of target transcripts. Four such proteins are found in mice, of which the best studied is TTP. When the gene encoding TTP is disrupted in mice, the animals develop a severe syndrome of arthritis, autoimmunity, cachexia, dermatitis, and myeloid hyperplasia. Conversely, recent overexpression studies have demonstrated protection against several experimental models of immune inflammatory disease. This endogenous anti-inflammatory protein could serve as the basis for novel approaches to therapy of similar conditions in humans.
Jean-jacques Feige - One of the best experts on this subject based on the ideXlab platform.
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Multiple functions of Tristetraprolin/TIS11 RNA-binding proteins in the regulation of mRNA biogenesis and degradation
Cellular and Molecular Life Sciences, 2013Co-Authors: Delphine Ciais, Nadia Cherradi, Jean-jacques FeigeAbstract:Members of the Tristetraprolin (TTP/TIS11) family are important RNA-binding proteins initially characterized as mediators of mRNA degradation. They act via their interaction with AU-rich elements present in the 3′UTR of regulated transcripts. However, it is progressively appearing that the different steps of mRNA processing and fate including transcription, splicing, polyadenylation, translation, and degradation are coordinately regulated by multifunctional integrator proteins that possess a larger panel of functions than originally anticipated. Tristetraprolin and related proteins are very good examples of such integrators. This review gathers the present knowledge on the functions of this family of RNA-binding proteins, including their role in AU-rich element-mediated mRNA decay and focuses on recent advances that support the concept of their broader involvement in distinct steps of mRNA biogenesis and degradation.
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multiple functions of Tristetraprolin tis11 rna binding proteins in the regulation of mrna biogenesis and degradation
Cellular and Molecular Life Sciences, 2013Co-Authors: Delphine Ciais, Jean-jacques Feige, Nadia CherradiAbstract:Members of the Tristetraprolin (TTP/TIS11) family are important RNA-binding proteins initially characterized as mediators of mRNA degradation. They act via their interaction with AU-rich elements present in the 3′UTR of regulated transcripts. However, it is progressively appearing that the different steps of mRNA processing and fate including transcription, splicing, polyadenylation, translation, and degradation are coordinately regulated by multifunctional integrator proteins that possess a larger panel of functions than originally anticipated. Tristetraprolin and related proteins are very good examples of such integrators. This review gathers the present knowledge on the functions of this family of RNA-binding proteins, including their role in AU-rich element-mediated mRNA decay and focuses on recent advances that support the concept of their broader involvement in distinct steps of mRNA biogenesis and degradation.
Sonika Patial - One of the best experts on this subject based on the ideXlab platform.
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The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects.
Cancers, 2020Co-Authors: Yogesh Saini, Jian Chen, Sonika PatialAbstract:Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The Tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as Tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.
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Tristetraprolin as a Therapeutic Target in Inflammatory Disease
Trends in pharmacological sciences, 2016Co-Authors: Sonika Patial, Perry J. BlackshearAbstract:Members of the Tristetraprolin (TTP) family of RNA-binding proteins are found in all major eukaryotic groups. TTP family members, from plants through humans, can bind adenosine-uridine rich elements in target mRNAs with high affinity. In mammalian cells, these proteins then promote deadenylation and decay of target transcripts. Four such proteins are found in mice, of which the best studied is TTP. When the gene encoding TTP is disrupted in mice, the animals develop a severe syndrome of arthritis, autoimmunity, cachexia, dermatitis, and myeloid hyperplasia. Conversely, recent overexpression studies have demonstrated protection against several experimental models of immune inflammatory disease. This endogenous anti-inflammatory protein could serve as the basis for novel approaches to therapy of similar conditions in humans.
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Genetic deletion of an instability motif in the Tristetraprolin (TTP) transcript increases TTP mRNA stability and protein expression and provides protection against inflammatory diseases
The FASEB Journal, 2015Co-Authors: Sonika Patial, Perry J. BlackshearAbstract:Objective: Tristetraprolin (TTP) is an mRNA binding protein that binds to AU-rich elements (AREs) in the 3'-untranslated regions (3'UTR) of specific mRNAs, such as tumor necrosis factor (TNF) mRNA,...
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mTOR Regulates Cellular Iron Homeostasis through Tristetraprolin
Cell metabolism, 2012Co-Authors: Marina Bayeva, Perry J. Blackshear, Sonika Patial, Arineh Khechaduri, Sergi Puig, Hsiang Chun Chang, Hossein ArdehaliAbstract:Iron is an essential cofactor with unique redox properties. Iron-regulatory proteins 1 and 2 (IRP1/2) have been established as important regulators of cellular iron homeostasis, but little is known about the role of other pathways in this process. Here we report that the mammalian target of rapamycin (mTOR) regulates iron homeostasis by modulating transferrin receptor 1 (TfR1) stability and altering cellular iron flux. Mechanistic studies identify Tristetraprolin (TTP), a protein involved in anti-inflammatory response, as the downstream target of mTOR that binds to and enhances degradation of TfR1 mRNA. We also show that TTP is strongly induced by iron chelation, promotes downregulation of iron-requiring genes in both mammalian and yeast cells, and modulates survival in low-iron states. Taken together, our data uncover a link between metabolic, inflammatory, and iron-regulatory pathways, and point toward the existence of a yeast-like TTP-mediated iron conservation program in mammals.
Eeva Moilanen - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of protein kinase Cdelta reduces Tristetraprolin expression by destabilizing its mRNA in activated macrophages.
European journal of pharmacology, 2009Co-Authors: Tiina Leppänen, Ulla Jalonen, Riku Korhonen, Raimo K. Tuominen, Eeva MoilanenAbstract:Tristetraprolin (TTP) binds to AU-rich elements within the mRNAs of several inflammatory genes and causes destabilization of the target mRNAs. The protein kinase C (PKC) pathway represents a major signalling system in inflammation and PKCdelta is one of the key isoenzymes in the regulation of inflammatory processes. In the present study, we investigated the role of PKCdelta in the regulation of the expression of Tristetraprolin in activated macrophages by using the PKCdelta inhibitor, rottlerin, and by downregulating PKCdelta expression by using PKCdelta siRNA. TTP protein and mRNA expression were measured by Western blotting and quantitative RT-PCR, respectively. TTP and TNFalpha mRNA decays were studied by the actinomycin D assay. In addition, we measured nuclear translocation of transcription factors believed to be important for TTP transcription, i.e. NF-kappaB, AP-2, SP1 and EGR1. Downregulation of PKCdelta by siRNA decreased significantly TTP expression in activated macrophages. Rottlerin also decreased TTP expression in wild type cells but not in cells in which PKCdelta had been downregulated by siRNA. Rottlerin decreased TTP mRNA half-life as measured by actinomycin D assay but it did not affect the nuclear translocation of transcription factors NF-kappaB, Sp1, AP-2 or EGR1 (which have been shown to be involved in TTP transcription). In addition, rottlerin reduced the decay of TNFalpha mRNA, which is an important target of TTP. The results suggest that PKCdelta up-regulates the expression of TTP by stabilizing its mRNA which may serve as a feed-back loop to regulate the inflammatory response.
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Inhibition of protein kinase Cδ reduces Tristetraprolin expression by destabilizing its mRNA in activated macrophages
European Journal of Pharmacology, 2009Co-Authors: Tiina Leppänen, Ulla Jalonen, Riku Korhonen, Raimo K. Tuominen, Eeva MoilanenAbstract:Abstract Tristetraprolin (TTP) binds to AU-rich elements within the mRNAs of several inflammatory genes and causes destabilization of the target mRNAs. The protein kinase C (PKC) pathway represents a major signalling system in inflammation and PKCδ is one of the key isoenzymes in the regulation of inflammatory processes. In the present study, we investigated the role of PKCδ in the regulation of the expression of Tristetraprolin in activated macrophages by using the PKCδ inhibitor, rottlerin, and by downregulating PKCδ expression by using PKCδ siRNA. TTP protein and mRNA expression were measured by Western blotting and quantitative RT-PCR, respectively. TTP and TNFα mRNA decays were studied by the actinomycin D assay. In addition, we measured nuclear translocation of transcription factors believed to be important for TTP transcription, i.e. NF-κB, AP-2, SP1 and EGR1. Downregulation of PKCδ by siRNA decreased significantly TTP expression in activated macrophages. Rottlerin also decreased TTP expression in wild type cells but not in cells in which PKCδ had been downregulated by siRNA. Rottlerin decreased TTP mRNA half-life as measured by actinomycin D assay but it did not affect the nuclear translocation of transcription factors NF-κB, Sp1, AP-2 or EGR1 (which have been shown to be involved in TTP transcription). In addition, rottlerin reduced the decay of TNFα mRNA, which is an important target of TTP. The results suggest that PKCδ up-regulates the expression of TTP by stabilizing its mRNA which may serve as a feed-back loop to regulate the inflammatory response.
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Salbutamol increases Tristetraprolin expression in macrophages.
Life sciences, 2007Co-Authors: Ulla Jalonen, Tiina Leppänen, Hannu Kankaanranta, Eeva MoilanenAbstract:Tristetraprolin (TTP) is a tandem zinc finger protein that can bind to AU-rich elements (AREs) in the 3'-untranslated regions (3'-UTR) in mRNAs of transiently expressed genes, e.g. tumor necrosis factor-alpha (TNF-alpha) and granulocyte macrophage colony-stimulating factor (GM-CSF). TTP increases the turnover rate of the target mRNAs, thereby reducing, for example, the expression of TNF-alpha and GM-CSF. We examined the role of beta(2)-agonists, cAMP analogs, and forskolin (an activator of adenylate cyclase) on TTP mRNA and protein expression by quantitative real-time RT-PCR and Western blotting in J774 murine macrophages and THP-1 human macrophages. All of these agents increased TTP expression. A nonspecific inhibitor of phosphodiesterases (PDEs) 3-isobutyl-1-methylxanthine (IBMX) and type IV PDE-inhibitor rolipram further enhanced the increase in TTP expression levels, suggesting a cAMP-mediated effect. A possible mediator of these effects is transcription factor activator protein 2 (AP-2), whereas nuclear factor kappaB (NF-kappaB) seemed not to play any role. This mechanism may, at least in part, explain the anti-inflammatory effects which beta(2)-agonists have been reported to have in macrophages.
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Inhibition of Tristetraprolin expression by dexamethasone in activated macrophages.
Biochemical pharmacology, 2005Co-Authors: Ulla Jalonen, Hannu Kankaanranta, Riku Korhonen, Aleksi Lahti, Eeva MoilanenAbstract:Tristetraprolin (TTP) is a factor that regulates mRNA stability and the expression of certain inflammatory genes. In the present study, we found that TTP expression was increased in macrophages exposed to bacterial lipopolysaccharide (LPS). Dexamethasone and dissociated steroid RU24858 inhibited LPS-induced TTP protein and mRNA expression and the inhibitory effect was reversed by a glucocorticoid receptor antagonist mifepristone. Histone deacetylase inhibitors trichostatin A (TSA) and apicidin reduced the inhibitory effect of dexamethasone and RU24858 on TTP expression, but the glucocorticoids did not alter TTP mRNA half-life. These results suggest that anti-inflammatory steroids reduce TTP expression in activated macrophages by a glucocorticoid response element (GRE)-independent mechanism, possibly through histone deacetylation and transcriptional silencing.
Delphine Ciais - One of the best experts on this subject based on the ideXlab platform.
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Multiple functions of Tristetraprolin/TIS11 RNA-binding proteins in the regulation of mRNA biogenesis and degradation
Cellular and Molecular Life Sciences, 2013Co-Authors: Delphine Ciais, Nadia Cherradi, Jean-jacques FeigeAbstract:Members of the Tristetraprolin (TTP/TIS11) family are important RNA-binding proteins initially characterized as mediators of mRNA degradation. They act via their interaction with AU-rich elements present in the 3′UTR of regulated transcripts. However, it is progressively appearing that the different steps of mRNA processing and fate including transcription, splicing, polyadenylation, translation, and degradation are coordinately regulated by multifunctional integrator proteins that possess a larger panel of functions than originally anticipated. Tristetraprolin and related proteins are very good examples of such integrators. This review gathers the present knowledge on the functions of this family of RNA-binding proteins, including their role in AU-rich element-mediated mRNA decay and focuses on recent advances that support the concept of their broader involvement in distinct steps of mRNA biogenesis and degradation.
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multiple functions of Tristetraprolin tis11 rna binding proteins in the regulation of mrna biogenesis and degradation
Cellular and Molecular Life Sciences, 2013Co-Authors: Delphine Ciais, Jean-jacques Feige, Nadia CherradiAbstract:Members of the Tristetraprolin (TTP/TIS11) family are important RNA-binding proteins initially characterized as mediators of mRNA degradation. They act via their interaction with AU-rich elements present in the 3′UTR of regulated transcripts. However, it is progressively appearing that the different steps of mRNA processing and fate including transcription, splicing, polyadenylation, translation, and degradation are coordinately regulated by multifunctional integrator proteins that possess a larger panel of functions than originally anticipated. Tristetraprolin and related proteins are very good examples of such integrators. This review gathers the present knowledge on the functions of this family of RNA-binding proteins, including their role in AU-rich element-mediated mRNA decay and focuses on recent advances that support the concept of their broader involvement in distinct steps of mRNA biogenesis and degradation.
