Journal of Leukocyte Biology BioLegend: Treg, Th17, Stem Cell
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published online as doi:10.1189/jlb.1103536 on April 1, 2004

Published online before print April 1, 2004
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.1103536v1
76/1/42    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Anderson, P.
Right arrow Articles by Kedersha, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Anderson, P.
Right arrow Articles by Kedersha, N.
(Journal of Leukocyte Biology. 2004;76:42-47.)
© 2004 by Society for Leukocyte Biology

Post-transcriptional regulation of proinflammatory proteins

Paul Anderson1, Kristine Phillips, Georg Stoecklin and Nancy Kedersha

Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

1Correspondence: Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115. E-mail: panderson{at}rics.bwh.harvard.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 REFERENCES
 
Post-transcriptional mechanisms play a critical role in regulating the expression of numerous proteins that promote inflammatory arthritis. The mRNAs encoding a subset of these proteins possess adenine/uridine-rich elements (AREs) in their 3'-untranslated regions that profoundly influence the rate at which mRNA is degraded and translated into protein. Tristetraprolin (TTP) and T cell intracellular antigen-1 (TIA-1) are ARE-binding proteins that dampen the expression of this class of proteins by promoting mRNA degradation and protein translation, respectively. We have discovered that TIA-1 and TTP function as arthritis-suppressor genes: TIA-1–/– mice develop mild arthritis, TTP–/– mice develop severe arthritis, and TIA-1–/–TTP–/– mice develop very severe arthritis. Paradoxically, lipopolysaccharide (LPS)-activated macrophages derived from TIA-1–/–TTP–/– macrophages produce less tumor necrosis factor {alpha} (TNF-{alpha}) than TIA-1–/– or TTP–/– macrophages. The bone marrows of these mice exhibit increased cellularity, reflecting the presence of mature neutrophils that secrete TNF-{alpha} in response to LPS stimulation. We hypothesize that TIA-1–/–TTP–/– neutrophils are a source of arthritigenic TNF-{alpha}, which promotes severe erosive arthritis in these mice.

Key Words: tristetraprolin • T cell intracellular antigen-1 • adenine/uridine-rich elements


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
REFERENCES
 
In prokaryotes, the coordinate expression of genes encoding components of a metabolic pathway is often accomplished by expressing an mRNA transcript that encodes more than one protein. For example, the Lac operon in Escherichia coli transcribes a single mRNA that encodes ß-galactosidase, permease, and transacetylase, proteins required for the use of lactose as a carbon source [1 ]. Unlike their prokaryotic ancestors, processed eukaryotic transcripts generally encode a single protein. In eukaryotes, the coordinate expression of protein components of a complex functional program such as the inflammatory response is accomplished by the use of regulatory nucleic acid sequences that determine rates of transcription, translation, and mRNA decay. During the typical inflammatory response, coordinate transcriptional control is accomplished by the selective use of promoter elements that are recognized by specific transcription factors. For example, the transcription factor nuclear factor (NF)-{kappa}B moves from the cytoplasm to the nucleus in T cells and macrophages that are exposed to inflammatory stimuli [2 ]. Nuclear NF-{kappa}B binds to a nucleotide sequence element common to the promoters of several genes that encode inflammatory effector proteins [3 ]. Mammalian cells have evolved post-transcriptional mechanisms that further regulate the expression of these potentially injurious proteins. Post-transcriptional control is usually conferred by cis-acting elements located in the 3'-untranslated regions (UTR) of these transcripts. An important example is the adenine/uridine-rich element (ARE), a cis-acting element composed of AUUUA repeats, which dampens protein expression by promoting mRNA decay and inhibiting protein translation [4 ]. Expression of proteins encoded by ARE-containing transcripts requires the regulated suppression of ARE-dependent, inhibitory mechanisms [5 ].

Several proteins that are encoded by ARE-containing transcripts are critical components of the effector phase of inflammatory arthritis. Of particular importance is tumor necrosis factor {alpha} (TNF-{alpha}), a proinflammatory cytokine produced by activated macrophages, mast cells, and lymphocytes [6 , 7 ]. TNF-{alpha} expression is regulated transcriptionally and post-transcriptionally [8 9 10 11 ]. Post-transcriptional control of TNF-{alpha} expression requires the ARE-dependent regulation of mRNA stability and translation [8 , 9 ]. Transgenic mice expressing TNF-{alpha} transcripts lacking the ARE develop chronic inflammatory polyarthritis and inflammatory bowel disease, a consequence of pathological overexpression of TNF-{alpha} [9 ]. Neutralizing antibodies to TNF-{alpha} prevent arthritis in this animal model [12 , 13 ]. Thus, abrogation of ARE-dependent, post-transcriptional control of TNF-{alpha} production is sufficient to induce the onset of inflammatory arthritis in mice. These preclinical studies provided the rationale for clinical trials that established the efficacy of TNF-{alpha} blockade in patients with rheumatoid arthritis [14 ].

ARE-dependent, post-transcriptional mechanisms also regulate the production of cyclooxygenase-2 (COX-2) [15 , 16 ] and matrix metalloproteinase-13 (MMP-13) [16 ]. COX-2 is an enzyme that converts arachidonic acid into proinflammatory prostaglandins [17 , 18 ]. Pharmacologic inhibitors of COX-2 are potent, anti-inflammatory agents, which significantly reduce the severity of inflammatory arthritis [17 ]. MMP-13 is a TNF-{alpha}-induced collagenase that has been implicated in proinflammatory, angiogenic, and destructive processes within the joint of patients with rheumatoid arthritis [19 20 21 22 ]. Thus, ARE-dependent, post-transcriptional mechanisms can coordinately regulate the expression of metabolic enzymes and proteases as well as proinflammatory cytokines. An understanding of the molecular mechanisms of ARE-dependent, post-transcriptional control should identify new targets for the development of anti-inflammatory drugs.

Trans-acting factors that bind to the ARE are essential determinants of mRNA stability and translational competence [4 ]. Individual ARE-binding proteins can promote or inhibit the expression of inflammatory effector proteins. ARE-binding proteins that dampen the expression of inflammatory effectors may suppress inflammatory arthritis. The best characterized examples of inhibitory ARE-binding proteins are tristetraprolin (TTP; GenBank accession #NP003398), T cell intracellular antigen-1 (TIA-1; GenBank accession #NP071320), and TIA-1-related (TIAR; GenBank accession #NP003243). TTP is a zinc-finger protein that promotes the degradation of TNF-{alpha} transcripts [23 24 25 26 ]. In macrophages, its induction by lipopolysaccharide (LPS) appears to prevent the pathological overexpression of this proinflammatory cytokine [23 ]. Mice lacking TTP develop an autoimmune syndrome characterized by cachexia, arthritis, dermatitis, and autoantibody formation [27 ]. Arthritis is prevented by neutralizing antibodies against TNF-{alpha} and is not observed in TTP–/–TNF receptor-1–/– mice, indicating that TNF-{alpha} is essential for the development of inflammatory arthritis [28 ]. In macrophages lacking TTP, TNF-{alpha} transcripts are stabilized, resulting in the pathological overexpression of TNF-{alpha} mRNA and protein [23 , 27 ]. Like TNF-{alpha} transcripts, granulocyte macropahge-colony stimulating factor (GM-CSF) transcripts are destabilized by TTP [29 ]. Overproduction of GM-CSF by bone marrow stromal cells activates medulary and extramedulary granulopoiesis [27 ], causing abnormal accumulations of mature neutrophils in the bone marrow, lymph nodes, spleen, and peripheral blood.

TIA-1 and TIAR are closely related members of the RNA recognition-motif family of RNA-binding proteins, which inhibit the translation of TNF-{alpha} transcripts in macrophages [30 31 32 ] but not in T lymphocytes [33 ]. BALB/c mice lacking TIA-1 are phenotypically normal [32 ]. Although LPS-activated macrophages derived from wild-type and TIA-1–/– mice express similar amounts of TNF-{alpha} transcripts, macrophages lacking TIA-1 produce significantly more TNF-{alpha} protein than wild-type controls [32 , 33 ]. In macrophages lacking TIA-1, the percentage of TNF-{alpha} transcripts found in polysomes is significantly increased, suggesting that TIA-1 functions as a translational silencer [32 ]. The overexpression of TNF-{alpha} protein in macrophages lacking TIA-1 is strain-dependent. TIA-1–/– macrophages derived from BALB/c mice produce three to five times more TNF-{alpha} than wild-type controls, whereas TIA-1–/– macrophages derived from C57BL/6 mice produce nearly 10 times more TNF-{alpha} than wild-type controls [33 ]. Moreover, C57BL/6 mice spontaneously develop mild arthritis [34 ]. Thus, unidentified genetic modifiers determine whether TIA-1–/– mice develop arthritis.

Much of what we know about the mechanism of TIA-1-induced translational repression comes from studies of the general translational arrest triggered by environmental stress (e.g., heat, oxidative conditions, energy deprivation) [30 , 31 , 35 ]. Stress-induced translational arrest is characterized by the activation of one or more members of a family of serine/threonine kinases [e.g., double-stranded RNA-dependent protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), GCN2, and heme-regulated inhibitor kinase; refs. 36 37 38 39 ]. These kinases phosphorylate eukaryotic initiation factor 2{alpha} (eIF2{alpha}), a component of the ternary complex that loads tRNAiMet onto the small ribosomal subunit to initiate protein synthesis [40 ]. Phosphorylation of eIF2{alpha} inhibits protein translation by reducing the availability of an active ternary complex [41 ]. Under these conditions, TIA-1 promotes the assembly of a noncanonical translation-initiation complex that is directed to discrete cytoplasmic foci known as stress granules (SGs) [31 ], as shown in the model illustrated in Figure 1A (depicting normal translation initiation and Figure 1B (depicting translation–initiation during stress) [42 43 44 ]. This model predicts that TIA-1 interacts with specific components of the initiation complex that are assembled at the 5'-end of the transcript. By tethering TIA-1 to the 3'-end of selected transcripts, the ARE appears to increase the likelihood that TIA-1 will assemble a translationally incompetent complex at the 5'-end of the transcript [32 ] (Fig. 1C) . Although SGs are visible only when large numbers of transcripts are simultaneously subjected to translational arrest, the underlying translational control mechanism (i.e., assembly of stalled initiation complexes) regulates protein expression in stressed and unstressed cells [30 , 31 ].



View larger version (22K):
[in this window]
[in a new window]
  		Figure 1. Schematic depiction of translational initiation in the absence (A) or presence (B) of stress. In the absence of stress, the 48S preinitiation complex assembles at the 5'-end of the transcript, scans to the AUG start codon, and then recruits the large ribosomal subunit. Under stress conditions, phosphorylation of eIF2{alpha} results in the depletion of the eIF2–guanosine 5'-triphosphate (GTP)–tRNA–Met ternary complex and assembly of a noncanonical 48S preinitiation complex that is routed to SGs. (C) TIA-1 is tethered transcripts containing AREs in their 3'-UTR. This increases the assembly of the stalled translation-initiation complex and inhibits protein synthesis. GDP, Guanosine 5'-diphosphate; PKR, protein kinase R; 1, 2, 3, 4, 5: translation initiation factors.

 
In activated macrophages, expression of proteins encoded by ARE-containing transcripts requires activation of the p38-mitogen-activated protein kinase (MAPK)/MAPK-activated protein (MAPKAP) kinase-2 cascade (Fig. 2 ) [9 , 10 , 45 46 47 48 49 ]. As a consequence, pharmacological inhibitors of p38MAPK prevent the expression of TNF-{alpha}, COX-2, MMP-13, and other proinflammatory proteins [50 51 52 53 54 55 ]. Activation of p38MAPK stabilizes and promotes the translation of ARE-containing transcripts. One of the candidate substrates for p38MAPK is TTP [56 , 57 ]. In extracts of 293 cells, calf intestinal alkaline phosphatase-induced dephosphorylation of recombinant TTP increases its affinity for AREs [56 ]. This result suggests that phosphorylation of TTP might prevent it from binding to ARE transcripts.



View larger version (17K):
[in this window]
[in a new window]
  		Figure 2. Schematic depiction of post-transcriptional regulation of ARE-containing transcripts encoding proinflammatory proteins. CSAID, Cytokine-suppressive anti-inflammatory drug; ARE-BP: AU-rich element-binding protein; PAK, p21-activated kinase; MKK, MAPK kinase; MK2, MAPKAP kinase 2.

 
We have discovered that TTP is also a component of SGs [58 ]. TTP is recruited to SGs assembled in response to p-trifluoromethoxyphenyl hydrazone, a metabolic poison that reduces the availability of cellular adenosine 5'-triphosphate. In contrast, TTP is not recruited to SGs assembled in response to arsenite-induced oxidative stress. The exclusion of TTP from arsenite-induced SGs was found to be a consequence of arsenite-induced activation of the p38MAPK/MK2 kinase cascade. We found that MK2-induced phosphorylation of TTP results in the assembly of 14-3-3:TTP complexes, which are actively excluded from SGs. We identified serine residues 52 and 178 as sites that are phosphorylated following p38MAPK/MK2 activation to create 14-3-3-binding sites. When these sites are mutated to alanine residues (TTP-AA), the mutant TTP is recruited to arsenite-induced SGs. The TTP-AA mutant is more effective than wild-type TTP at promoting the degradation of ARE-containing transcripts, suggesting that 14-3-3 binding negatively regulates the function of TTP. Thus, exclusion of TTP from SGs correlates with inhibition of TTP activity, which suggests that TTP induces the degradation of translationally stalled mRNAs. Figure 3 shows a schematic depiction of the role of TTP:14-3-3 complexes in the regulation of TTP function. In this model, the p38MAPK/MK2 kinase cascade determines whether TTP can associate with ARE-containing transcripts in SGs. SG-associated transcripts that bind to TTP are thought to be selectively delivered to a degradative pathway.



View larger version (27K):
[in this window]
[in a new window]
  		Figure 3. Model depicting the role of the p38MAPK/MK2 kinase cascade in the regulation of TTP function. MK2-induced phosphorylation of TTP results in the acquisition of two 14-3-3-binding sites. The TTP:14-3-3 complex is sequestered from SGs, resulting in the stabilization of ARE-containing transcripts.

 
At the SG the composition of messenger ribonucleoprotein (mRNP) particles is monitored to determine whether individual transcripts will be degraded, reinitiated, or stored. Although SGs are microscopically visible in cells subjected to environmental stress, the underlying regulatory mechanism (i.e., assembly of stalled translation-initiation complexes) may also occur in unstressed cells. Indeed, this process may determine how many times a polysomal mRNA is translated before it is disassembled and degraded. We hypothesize that mRNPs that include destabilizing proteins (e.g., TTP) will be targeted for degradation, whereas mRNPs that include stabilizing proteins (e.g., HuR) will be reinitiated. This process requires that the regulation of mRNA stability and mRNA translation must be closely linked.

Mutant mice lacking TTP and TIA-1 develop spontaneous inflammatory arthritis that is significantly more severe than the arthritis observed in mice lacking TIA-1 or TTP alone [34 ]. Although macrophages derived from TIA-1–/–/TTP–/– mice overexpress TNF-{alpha} mRNA, they express less TNF-{alpha} protein than TIA-1–/– or TTP–/– macrophages [34 ]. Whether this results from defective nuclear export of TNF-{alpha} transcripts, defective translation, or defective processing of TNF-{alpha} protein remains to be determined. The source of arthritigenic cytokine in mice lacking TIA-1 and TTP may be an expanded population of neutrophils found in the bone marrow and peripheral blood. The marked increase in neutrophils observed in TTP–/– bone marrow and peripheral blood is potentiated in mice that also lack TIA-1. The mechanism whereby TIA-1 and TTP cooperate to increase the maturation and/or survival of neutrophils is not known. Whereas wild-type neutrophils produce little or no TNF-{alpha} in response to LPS stimulation, neutrophils lacking TTP secrete significant amounts of TNF-{alpha} in response to LPS [34 ]. It is therefore possible that neutrophils are an important source of this proarthritic cytokine in mice lacking TIA-1 and TTP.

Although neutrophils clearly contribute to the pathogenesis of arthritis [59 , 60 ], our understanding of their precise contribution to the inflammatory process is incomplete. Neutrophils are the predominant cell type found in inflammatory synovial fluid (but not synovial pannus) derived from patients with rheumatoid arthritis. They are an important source of arachadonic acid-derived inflammatory mediators (e.g., prostaglandins, leukotrienes, and lipoxins). They are essential components of the inflammatory process in animal models of inflammatory arthritis [61 ]. The ability of TIA-1 and TTP to cooperatively regulate neutrophil maturation and function suggests that these cells could be a major source of inflammatory cytokine production in a subset of patients with rheumatoid arthritis.

Received November 4, 2003; revised January 6, 2004; accepted January 29, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 REFERENCES
 

  1. Beckwith, J. R. (1967) Regulation of the lac operon. Recent studies on the regulation of lactose metabolism in Escherichia coli support the operon model Science 156,597-604[Free Full Text]
  2. Muller-Ladner, U., Gay, R. E., Gay, S. (2002) Role of nuclear factor {kappa}B in synovial inflammation Curr. Rheumatol. Rep. 4,201-207[Medline]
  3. Muller, C. W. (2001) DNA recognition by NF {kappa} B and STAT transcription factors Ernst Schering Res. Found. Workshop 34,143-166
  4. Zhang, T., Kruys, V., Huez, G., Gueydan, C. (2002) AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors Biochem. Soc. Trans. 30,952-958[CrossRef][Medline]
  5. Kotlyarov, A., Gaestel, M. (2002) Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? Biochem. Soc. Trans. 30,959-963[CrossRef][Medline]
  6. Kassiotis, G., Kollias, G. (2001) TNF and receptors in organ-specific autoimmune disease: multi-layered functioning mirrored in animal models J. Clin. Invest. 107,1507-1508[Medline]
  7. Kollias, G., Douni, E., Kassiotis, G., Kontoyiannis, D. (1999) The function of TNF and receptors in models of multi-organ inflammation, rheumatoid arthritis, multiple scleroisis and inflammatory bowel disease Ann. Rheum. Dis. 58,I32-I39
  8. Jacob, C. O., Tashman, N. B. (1993) Disruption in the AU motif of the mouse TNF-{alpha} 3' UTR correlates with reduced TNF production by macrophages in vitro Nucleic Acids Res. 21,2761-2766[Abstract/Free Full Text]
  9. Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F., Kollias, G. (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies Immunity 10,387-398[CrossRef][Medline]
  10. Kraatz, J., Clair, L., Rodriguez, J. L., West, M. A. (1999) Macrophage TNF secretion in endotoxin tolerance: role of SAPK, p38, and MAPK J. Surg. Res. 83,158-164[CrossRef][Medline]
  11. Means, T., Pavlovich, R., Roca, D., Vermeulen, M., Fenton, M. (2000) Activation of TNF {alpha} transcription utilizes distinct MAP kinase pathways in different macrophage populations J. Leukoc. Biol. 67,885-893[Abstract]
  12. Keffer, J., Probert, L., Cazlaris, H., Georgopoulos, S., Kaslaris, E., Kioussis, D., Kollias, G. (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis EMBO J. 10,4025-4031[Medline]
  13. Kollias, G., Kontoyiannis, D., Douni, E., Kassiotis, G. (2002) The role of TNF/TNFR in organ-specific and systemic autoimmunity: implications for the design of optimized ‘anti-TNF’ therapies Curr. Dir. Autoimmun. 5,30-50[Medline]
  14. Feldmann, M., Maini, R. N. (2002) Discovery of TNF-{alpha} as a therapeutic target in rheumatoid arthritis: preclinical and clinical studies Joint Bone Spine 69,12-18[CrossRef][Medline]
  15. Dixon, D., Balch, G., Kedersha, N., Anderson, P., Zimmerman, G., Beauchamp, R., Prescott, S. (2003) Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1 J. Exp. Med. 198,475-481[Abstract/Free Full Text]
  16. Yu, Q., Cok, S. J., Zeng, C., Morrison, A. R. (2003) Translational repression of human matrix metalloproteinases-13 by an alternatively spliced form of T-cell-restricted intracellular antigen-related protein (TIAR) J. Biol. Chem. 278,1579-1584[Abstract/Free Full Text]
  17. Schnitzer, T. J., Hochberg, M. C. (2002) COX-2-selective inhibitors in the treatment of arthritis Cleve. Clin. J. Med. 69(Suppl. 1),SI20-SI30
  18. Sundy, J. S. (2001) COX-2 inhibitors in rheumatoid arthritis Curr. Rheumatol. Rep. 3,86-91[Medline]
  19. Vincenti, M. P., Brinckerhoff, C. E. (2002) Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors Arthritis Res. 4,157-164[CrossRef][Medline]
  20. Wernicke, D., Schulze-Westhoff, C., Brauer, R., Petrow, P., Zacher, J., Gay, S., Gromnica-Ihle, E. (2002) Stimulation of collagenase 3 expression in synovial fibroblasts of patients with rheumatoid arthritis by contact with a three-dimensional collagen matrix or with normal cartilage when coimplanted in NOD/SCID mice Arthritis Rheum. 46,64-74[CrossRef][Medline]
  21. Moore, B. A., Aznavoorian, S., Engler, J. A., Windsor, L. J. (2000) Induction of collagenase-3 (MMP-13) in rheumatoid arthritis synovial fibroblasts Biochim. Biophys. Acta 1502,307-318[Medline]
  22. Konttinen, Y. T., Salo, T., Hanemaaijer, R., Valleala, H., Sorsa, T., Sutinen, M., Ceponis, A., Xu, J. W., Santavirta, S., Teronen, O., Lopez-Otin, C. (1999) Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate Matrix Biol. 18,401-412[CrossRef][Medline]
  23. Carballo, E., Lai, W. S., Blackshear, P. J. (1998) Feedback inhibition of macrophage tumor necrosis factor-{alpha} production by tristetraprolin Science 281,1001-1005[Abstract/Free Full Text]
  24. Lai, W. S., Carballo, E., Strum, J. R., Kennington, E. A., Phillips, R. S., Blackshear, P. J. (1999) Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor {alpha} mRNA Mol. Cell. Biol. 19,4311-4323[Abstract/Free Full Text]
  25. Lai, W. S., Carballo, E., Thorn, J. M., Kennington, E. A., Blackshear, P. J. (2000) Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to AU-rich elements and destabilization of mRNA J. Biol. Chem. 275,17827-17837[Abstract/Free Full Text]
  26. Lai, W. S., Blackshear, P. J. (2001) Interactions of CCCH zinc finger proteins with mRNA: tristetraprolin-mediated AU-rich element-dependent mRNA degradation can occur in the absence of a poly(A) tail J. Biol. Chem. 276,23144-23154[Abstract/Free Full Text]
  27. Carballo, E., Gilkeson, G. S., Blackshear, P. J. (1997) Bone marrow transplantation reproduces the tristetraprolin-deficiency syndrome in recombination activating gene-2 (–/–) mice. Evidence that monocyte/macrophage progenitors may be responsible for TNF{alpha} overproduction J. Clin. Invest. 100,986-995[Medline]
  28. Carballo, E., Blackshear, P. J. (2001) Roles of tumor necrosis factor-{alpha} receptor subtypes in the pathogenesis of the tristetraprolin-deficiency syndrome Blood 98,2389-2395[Abstract/Free Full Text]
  29. Carballo, E., Lai, W. S., Blackshear, P. J. (2000) Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability Blood 95,1891-1899[Abstract/Free Full Text]
  30. Anderson, P., Kedersha, N. (2002) Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation Cell Stress Chaperones 7,213-221[CrossRef][Medline]
  31. Anderson, P., Kedersha, N. (2002) Stressful initiations J. Cell Sci. 115,3227-3234[Abstract/Free Full Text]
  32. Piecyk, M., Wax, S., Beck, A. R., Kedersha, N., Gupta, M., Maritim, B., Chen, S., Gueydan, C., Kruys, V., Streuli, M., Anderson, P. (2000) TIA-1 is a translational silencer that selectively regulates the expression of TNF-{alpha} EMBO J. 19,4154-4163[CrossRef][Medline]
  33. Saito, K., Chen, S., Piecyk, M., Anderson, P. (2001) TIA-1 regulates the production of tumor necrosis factor {alpha} in macrophages, but not in lymphocytes Arthritis Rheum. 44,2879-2887[CrossRef][Medline]
  34. Phillips, K., Kedersha, N., Shen, L., Blackshear, P. J., Anderson, P. (2004) Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor {{alpha}}, cyclooxygenase 2, and inflammatory arthritis Proc. Natl. Acad. Sci. USA 101,2011-2016[Abstract/Free Full Text]
  35. Kedersha, N., Anderson, P. (2002) Stress granules: sites of mRNA triage that regulate mRNA stability and translatability Biochem. Soc. Trans. 30,963-969[CrossRef][Medline]
  36. Williams, B. R. (1999) PKR; a sentinel kinase for cellular stress Oncogene 18,6112-6120[CrossRef][Medline]
  37. Sood, R., Porter, A. C., Olsen, D. A., Cavener, D. R., Wek, R. C. (2000) A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2{alpha} Genetics 154,787-801[Abstract/Free Full Text]
  38. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., Ron, D. (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response Mol. Cell 5,897-904[CrossRef][Medline]
  39. Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M., Ron, D. (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells Mol. Cell 6,1099-1108[CrossRef][Medline]
  40. Dever, T. E. (2002) Gene-specific regulation by general translation factors Cell 108,545-556[CrossRef][Medline]
  41. Krishnamoorthy, T., Pavitt, G. D., Zhang, F., Dever, T. E., Hinnebusch, A. G. (2001) Tight binding of the phosphorylated {alpha} subunit of initiation factor 2 (eIF2{alpha}) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation Mol. Cell. Biol. 21,5018-5030[Abstract/Free Full Text]
  42. Kedersha, N. L., Gupta, M., Li, W., Miller, I., Anderson, P. (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2{alpha} to the assembly of mammalian stress granules J. Cell Biol. 147,1431-1441[Abstract/Free Full Text]
  43. Kedersha, N., Cho, M. R., Li, W., Yacono, P. W., Chen, S., Gilks, N., Golan, D. E., Anderson, P. (2000) Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules J. Cell Biol. 151,1257-1268[Abstract/Free Full Text]
  44. Kedersha, N., Chen, S., Gilks, N., Li, W., Miller, I. J., Stahl, J., Anderson, P. (2002) Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules Mol. Biol. Cell 13,195-210[Abstract/Free Full Text]
  45. Kontoyiannis, D., Kotlyarov, A., Carballo, E., Alexopoulou, L., Blackshear, P. J., Gaestel, M., Davis, R., Flavell, R., Kollias, G. (2001) Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology EMBO J. 20,3760-3770[CrossRef][Medline]
  46. Rousseau, S., Morrice, N., Peggie, M., Campbell, D. G., Gaestel, M., Cohen, P. (2002) Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs EMBO J. 21,6505-6514[CrossRef][Medline]
  47. Sato, K., Nagayama, H., Tadokoro, K., Juji, T., Takahashi, T. (1999) Extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and p38mapk are involved in IL-10-mediated selective repression of TNF-{alpha}-induced activation and maturation of human peripheral blood monocyte-derived dendritic cells J. Immunol. 162,3865-3872[Abstract/Free Full Text]
  48. Suzuki, M., Tetsuka, T., Yoshida, S., Watanabe, N., Kobayashi, M., Matsui, N., Okamoto, T. (2000) The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-{alpha}- or IL-1ß-stimulated rheumatoid synovial fibroblasts FEBS Lett. 465,23-27[CrossRef][Medline]
  49. Stoecklin, G., Lu, M., Rattenbacher, B., Moroni, C. (2003) A constitutive decay element promotes tumor necrosis factor {alpha} mRNA degradation via an AU-rich element-independent pathway Mol. Cell. Biol. 23,3506-3515[Abstract/Free Full Text]
  50. Denkert, C., Koch, I., Berger, S., Kobel, M., Siegert, A., Hauptmann, S. (2003) Cytokine-suppressive anti-inflammatory drugs (CSAIDs) inhibit invasion and MMP-1 production of ovarian carcinoma cells Cancer Lett. 195,101-109[CrossRef][Medline]
  51. Reunanen, N., Li, S. P., Ahonen, M., Foschi, M., Han, J., Kahari, V. M. (2002) Activation of p38 {alpha} MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization J. Biol. Chem. 277,32360-32368[Abstract/Free Full Text]
  52. Holvoet, S., Vincent, C., Schmitt, D., Serres, M. (2003) The inhibition of MAPK pathway is correlated with down-regulation of MMP-9 secretion induced by TNF-{alpha} in human keratinocytes Exp. Cell Res. 290,108-119[CrossRef][Medline]
  53. Foster, M. L., Halley, F., Souness, J. E. (2000) Potential of p38 inhibitors in the treatment of rheumatoid arthritis Drug News Perspect. 13,488-497[Medline]
  54. Ropert, C., Closel, M., Chaves, A. C., Gazzinelli, R. T. (2003) Inhibition of a p38/stress-activated protein kinase-2-dependent phosphatase restores function of IL-1 receptor-associate kinase-1 and reverses Toll-like receptor 2- and 4-dependent tolerance of macrophages J. Immunol. 171,1456-1465[Abstract/Free Full Text]
  55. Laufer, S. A., Wagner, G. K., Kotschenreuther, D. A., Albrecht, W. (2003) Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes J. Med. Chem. 46,3230-3244[CrossRef][Medline]
  56. Carballo, E., Cao, H., Lai, W. S., Kennington, E. A., Campbell, D., Blackshear, P. J. (2001) Decreased sensitivity of tristetraprolin-deficient cells to p38 inhibitors suggests the involvement of tristetraprolin in the p38 signaling pathway J. Biol. Chem. 276,42580-42587[Abstract/Free Full Text]
  57. Mahtani, K. R., Brook, M., Dean, J. L., Sully, G., Saklatvala, J., Clark, A. R. (2001) Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor {alpha} mRNA stability Mol. Cell. Biol. 21,6461-6469[Abstract/Free Full Text]
  58. Stoecklin, G., Stubbs, T., Kedersha, N., Wax, S., Rigby, W. F. C., Blackwell, T. K., Anderson, P. (2004) Mk2-induced tristraprolin: 14-3-3 complexes present stress granule association and ARE-mRNA decay EMBO J. (in press).
  59. Edwards, M. C., Liegeois, N., Horecka, J., DePinho, R. A., Sprague, G. F., Jr, Tyers, M., Elledge, S. J. (1997) Human CPR (cell cycle progression restoration) genes impart a Far– phenotype on yeast cells Genetics 147,1063-1076[Abstract]
  60. Pillinger, M., Abramson, S. (1995) The neutrophil in rheumatoid arthritis Rheum. Dis. Clin. North Am. 21,691-714[Medline]
  61. Wipke, B. T., Allen, P. M. (2001) Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis J. Immunol. 167,1601-1608[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Respir. Cell Mol. Bio.Home page
A.-M. Pulichino, I-M. Wang, A. Caron, J. Mortimer, A. Auger, Y. Boie, J. A. Elias, A. Kartono, L. Xu, J. Menetski, et al.
Identification of Transforming Growth Factor {beta}1-Driven Genetic Programs of Acute Lung Fibrosis
Am. J. Respir. Cell Mol. Biol., September 1, 2008; 39(3): 324 - 336.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S.-D. Ha, A. Martins, K. Khazaie, J. Han, B. M. C. Chan, and S. O. Kim
Cathepsin B Is Involved in the Trafficking of TNF-{alpha}-Containing Vesicles to the Plasma Membrane in Macrophages
J. Immunol., July 1, 2008; 181(1): 690 - 697.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
N. Lahat, M. A. Rahat, A. Kinarty, L. Weiss-Cerem, S. Pinchevski, and H. Bitterman
Hypoxia enhances lysosomal TNF-{alpha} degradation in mouse peritoneal macrophages
Am J Physiol Cell Physiol, July 1, 2008; 295(1): C2 - C12.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Datta, R. Biswas, M. Novotny, P. G. Pavicic Jr., T. Herjan, P. Mandal, and T. A. Hamilton
Tristetraprolin Regulates CXCL1 (KC) mRNA Stability
J. Immunol., February 15, 2008; 180(4): 2545 - 2552.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
H. Dombrowsky and S. Uhlig
Steroids and histone deacetylase in ventilation-induced gene transcription
Eur. Respir. J., November 1, 2007; 30(5): 865 - 877.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
T. A. Hamilton, M. Novotny, S. Datta, P. Mandal, J. Hartupee, J. Tebo, and X. Li
Chemokine and chemoattractant receptor expression: post-transcriptional regulation
J. Leukoc. Biol., August 1, 2007; 82(2): 213 - 219.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. Frasca, A. M. Landin, J. P. Alvarez, P. J. Blackshear, R. L. Riley, and B. B. Blomberg
Tristetraprolin, a Negative Regulator of mRNA Stability, Is Increased in Old B Cells and Is Involved in the Degradation of E47 mRNA
J. Immunol., July 15, 2007; 179(2): 918 - 927.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Zhao and T. Hamilton
Introns Regulate the Rate of Unstable mRNA Decay
J. Biol. Chem., July 13, 2007; 282(28): 20230 - 20237.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
I. Sauer, B. Schaljo, C. Vogl, I. Gattermeier, T. Kolbe, M. Muller, P. J. Blackshear, and P. Kovarik
Interferons limit inflammatory responses by induction of tristetraprolin
Blood, June 15, 2006; 107(12): 4790 - 4797.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
K. Mazan-Mamczarz, A. Lal, J. L. Martindale, T. Kawai, and M. Gorospe
Translational Repression by RNA-Binding Protein TIAR.
Mol. Cell. Biol., April 1, 2006; 26(7): 2716 - 2727.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
P. J. Barnes
Corticosteroid effects on cell signalling
Eur. Respir. J., February 1, 2006; 27(2): 413 - 426.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Z. H. Nemeth, C. S. Lutz, B. Csoka, E. A. Deitch, S. J. Leibovich, W. C. Gause, M. Tone, P. Pacher, E. S. Vizi, and G. Hasko
Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism
J. Immunol., December 15, 2005; 175(12): 8260 - 8270.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
I. Lopez de Silanes, S. Galban, J. L. Martindale, X. Yang, K. Mazan-Mamczarz, F. E. Indig, G. Falco, M. Zhan, and M. Gorospe
Identification and Functional Outcome of mRNAs Associated with RNA-Binding Protein TIA-1
Mol. Cell. Biol., November 1, 2005; 25(21): 9520 - 9531.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
M. Baudouin-Legros, A. Hinzpeter, A. Jaulmes, F. Brouillard, B. Costes, P. Fanen, and A. Edelman
Cell-specific posttranscriptional regulation of CFTR gene expression via influence of MAPK cascades on 3'UTR part of transcripts
Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1240 - C1250.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Z. Murray, F. G. Wylie, T. Khromykh, D. A. Hume, and J. L. Stow
Syntaxin 6 and Vti1b Form a Novel SNARE Complex, Which Is Up-regulated in Activated Macrophages to Facilitate Exocytosis of Tumor Necrosis Factor-{alpha}
J. Biol. Chem., March 18, 2005; 280(11): 10478 - 10483.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
G. Grutz
New insights into the molecular mechanism of interleukin-10-mediated immunosuppression
J. Leukoc. Biol., January 1, 2005; 77(1): 3 - 15.
[Abstract] [Full Text] [PDF]

Home page
 RNAHome page
K. E. BAKER and C. CONDON
Under the Tucson sun: A meeting in the desert on mRNA decay
RNA, November 18, 2004; 10(11): 1680 - 1691.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.1103536v1
76/1/42    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Anderson, P.
Right arrow Articles by Kedersha, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Anderson, P.
Right arrow Articles by Kedersha, N.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS