Disease relevance of Zfp36

• Mice made deficient in TTP by gene targeting appeared normal at birth, but soon manifested marked medullary and extramedullary myeloid hyperplasia associated with cachexia, erosive arthritis, dermatitis, conjunctivitis, glomerular mesangial thickening, and high titers of anti-DNA and antinuclear antibodies [1].
• Conversely, mice deficient in TTP develop a complex syndrome characterized by cachexia, myeloid hyperplasia, and joint and skin inflammation [2].
• The nucleoside transport-deficient S49 T lymphoma cell line, AE1, however, was almost as capable of incorporating thymidine into TTP as the wild type parent provided thymidine was administered at a sufficiently high concentration [3].
• Kinetic analysis of nucleotide incorporation catalyzed by the vaccinia enzyme revealed apparent Km values of 0.9, 2.9, 4.0, and 2.7 microM for dGTP, dATP, TTP, and dCTP, respectively [4].

High impact information on Zfp36

• Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin [5].
• Tristetraprolin (TTP) is a widely expressed potential transcription factor that contains two unusual CCCH zinc fingers and is encoded by the immediate-early response gene, Zfp-36 [1].
• A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency [1].
• Treatment of young TTP-deficient mice with antibodies to tumor necrosis factor alpha (TNF alpha) prevented the development of essentially all aspects of the phenotype [1].
• By using a model system of ARE dysfunction, we demonstrate that HuR does not alter the accumulation of target mRNAs in the absence of the destabilizing functions of Tristetraprolin but synergizes with the translational silencer TIA-1 to reduce the translation of cytokine mRNAs [6].

Biological context of Zfp36

• Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNFalpha through distinct pathways [7].
• Here we show that tristetraprolin (TTP), an ARE-binding protein that destabilizes ARE-mRNAs, is recruited to SGs that are assembled in response to FCCP-induced energy deprivation, but not arsenite-induced oxidative stress [8].
• Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element [9].
• Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability [10].
• The biosynthesis of TTP was accompanied by large changes in electrophoretic mobility consistent with progressive phosphorylation [11].

Anatomical context of Zfp36

• We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-alpha 3' untranslated region [10].
• TTP was originally identified on the basis of its massive but transient increase in mRNA levels following mitogen stimulation of fibroblasts [11].
• Confocal microscopy revealed that TTP accumulated in a vesicular pattern in the cytosol of the LPS-stimulated RAW 264.7 cells, and was occasionally seen in the cytosol of unstimulated dividing cells [11].
• Finally, we determined that, in response to LPS stimulation, human TTP moves onto the polysomes, and this movement occurs in the absence of 14-3-3 [12].
• To investigate the effects of primary sequence on the subcellular localization of these proteins, we constructed green fluorescent protein fusions with TTP, CMG1, and TIS11D; these were predominantly cytoplasmic when expressed in 293 or HeLa cells [13].

Associations of Zfp36 with chemical compounds

• Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms [10].
• In both LPS-treated RAW 264.7 macrophages and fetal calf serum-treated mouse embryonic fibroblasts, TTP protein was stable after induction, with minimal degradation occurring for several hours after treatment of the cells with cycloheximide [11].
• Moreover, IL-10 does not alter TNF mRNA stability, and its action does not require the presence of the stability-regulating ARE binding factor tristetraprolin, indicating a differential assembly of stability and translation determinants on the TNF ARE [14].
• On the basis of the nuclear magnetic resonance data, we propose a structure for the Nup475 metal-binding domain in which the zinc ion is coordinated by the conserved cysteines and histidine, and the conserved YKTEL motif forms a parallel sheet-like structure with the C terminus of this domain [15].
• Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment [16].

Physical interactions of Zfp36

• Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases [17].

Enzymatic interactions of Zfp36

• MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding [18].

Regulatory relationships of Zfp36

• Consistently, STAT1 is required for full expression of Ttp in response to LPS that stimulates both p38 MAPK and, indirectly, interferon signaling [19].
• Here we show that TTP deficiency also results in increased cellular production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and increased stability of its mRNA, apparently secondary to decreased deadenylation [20].
• Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6-/- cardiomyocytes [21].
• Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell hybridoma [22].
• We further show that IL-10 is a novel target regulated by TTP [23].

Other interactions of Zfp36

• This effect seems to require only the conserved TTP zinc finger region, and is characteristic of the related proteins TIS11b and TIS11d [7].
• Tristetraprolin and LPS-inducible CXC chemokine are rapidly induced in presumptive satellite cells in response to skeletal muscle injury [24].
• TTP expression precedes that of MyoD and is detected 30 minutes after injury [24].
• Moreover, the interaction of TTP with 14-3-3, which may limit entry into the stress granule, is not involved in the downstream message stabilization events [12].
• The CCCH tandem zinc finger protein, Zfp36l2, like its better-known relative tristetraprolin (TTP), can decrease the stability of AU-rich element-containing transcripts in cell transfection studies; however, its physiological importance is unknown [25].

Analytical, diagnostic and therapeutic context of Zfp36

• To identify other genes induced in synchronized C2C12 myoblasts we used differential display PCR and isolated LIX and TTP cDNAs [24].
• After a lag period of several months, marrow transplantation from the (-/-) but not the (+/+) mice resulted in the full syndrome associated with TTP deficiency, suggesting that hematopoietic progenitors are responsible for the development of the syndrome [26].
• Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained two or more conserved TTP binding sites; nine of these appeared to be stabilized on Northern blots [16].
• It is interesting that transverse constriction of the aorta provoked an increase in the expression of tristetraprolin, a homeostatic zinc finger protein that is known to destabilize TNF mRNA [27].
• The present studies evaluated the effect of mitogens on the subcellular localization of TTP using Western blotting of cellular nuclear and cytosolic fractions [28].

References