Disease relevance of ZFP36

• We hypothesized that genetic variations in ZFP36 are associated with autoimmune disease in humans [1].
• Differential effects of sodium butyrate on the transcription of the human TIS11 family of early-response genes in colorectal cancer cells [2].
• Identification of a member of the TIS11 early response gene family at the insertion point of a DNA fragment containing a gene for the T-cell receptor beta chain in an acute T-cell leukemia [3].
• This value was about twice that of TTP from E. coli [4].
• One of the identified genes, TTP, was selected for further analysis. cDNA was prepared from synovial tissues of 22 patients with RA and 22 with osteoarthritis (OA) [5].

Psychiatry related information on ZFP36

• Three MRI exams showed no correlate for her neurological symptoms except a small petechial cortical hemorrhage in the right parietooccipital gyrus which may account for her TTP-related anxiety disorder [6].
• Here we describe a case of a woman who developed a sporadic form of TTP-HUS during a treatment with bupropion for smoking cessation, successfully treated with plasma ex-change therapy [7].
• It was found that TTP was both statistically and clinically more effective in reducing pathology related to PTSD and that this superiority was maintained and, in fact, became more evident by 3-month follow-up [8].

High impact information on ZFP36

• The role of miR16 in ARE-RNA decay is sequence-specific and requires the ARE binding protein tristetraprolin (TTP) [9].
• Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, central nervous system abnormalities, and renal dysfunction [10].
• Prednisone alone was judged to be effective in 30 patients with mild TTP-HUS (two relapses and two deaths) [10].
• Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-alpha production from macrophages by destabilizing its messenger RNA [11].
• The accumulation of ARE-mRNAs in PBs is strongly enhanced when the mRNA decay machinery is rendered limiting by mRNA decay enzyme depletion or TTP/BRF-1 overexpression [12].

Chemical compound and disease context of ZFP36

• In the present study, we expressed human and mouse TTP as glutathione S-transferase and maltose-binding protein (MBP) fusion proteins in Escherichia coli, and purified them by affinity resins and Mono Q chromatography [13].
• CONCLUSIONS: Quinine is a common cause of drug-associated TTP-HUS and can cause death and chronic renal failure [14].
• Plasmid DNA containing the adenovirus type 2 genes for VA RNA was linearized at a site distal to the gene, end labeled with a biotin-nucleotide analog of TTP, and incubated with avidin to form an avidin-biotinylated DNA complex [15].
• BACKGROUND: We present a case report of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) developing in a kidney/pancreas transplant recipient after the initiation of treatment with clopidogrel for symptomatic coronary artery disease [16].
• Decrease in TTP pools mediated by 5-bromo-2'-deoxyuridine exposure in a human glioblastoma cell line [17].

Biological context of ZFP36

• Based on the sequence-verified ZFP36 genotypes, 34 haplotypes were constructed [1].
• The three known mammalian CCCH tandem zinc finger proteins of the tristetraprolin (TTP) class have recently been demonstrated to be mRNA-binding proteins [18].
• Conversely, these mRNAs are stabilized in TTP-deficient mice, leading to an inflammatory phenotype characterized by overproduction of these cytokines [18].
• This up-regulation was confirmed by reverse transcriptase-PCR analysis that revealed a rapid and transient induction of TTP mRNA by TGF-beta 1 in HuT78 cells, primary human T cells, and THP-1 macrophage-monocyte cells [19].
• To delineate the transcriptional regulation of the TTP gene, a 2.7-kb human TTP promoter region (-2682 to +56 bp relative to the transcription initiation site) was isolated [19].

Anatomical context of ZFP36

• In this communication, we report that butyrate has differential effects on the transcription of the three human TIS11 family members identified so far in T84 and HT-29 human colorectal cancer cell lines [2].
• ARE-mRNA localization in PBs is mediated by the TTP N- and C-terminal domains and occurs downstream from mRNA polysome release, which in itself is not sufficient for mRNA PB localization [12].
• We developed a cell-free system in which TTP and its related proteins stimulated the deadenylation of ARE-containing, polyadenylated transcripts [20].
• Here we report that glucocorticoids induce the synthesis of TTP mRNA and protein in A549 lung epithelial cells and in rat tissues [21].
• Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells [22].

Associations of ZFP36 with chemical compounds

• Third, TTP can nucleate PB formation on untranslated mRNAs even when other mRNAs are trapped in polysomes by cycloheximide treatment [12].
• They are also dispersed by inhibitors of translational elongation and share several protein components, including Fas-activated serine/threonine phosphoprotein, XRN1, eIF4E, and tristetraprolin (TTP) [23].
• The ability of TTP to promote transcript deadenylation required Mg(2+), but not ATP or prior capping of the RNA substrate [20].
• Dexamethasone treatment leads to a sustained induction of TTP mRNA expression that is abrogated by RU486 [21].
• Post-transcriptional regulation occurs by modulation of TNF-alpha mRNA stability via the binding of tristetraprolin (TTP) to the adenosine/uridine-rich elements found in the 3'-untranslated region of the TNF-alpha transcript [24].

Physical interactions of ZFP36

• Here we identify an evolutionarily conserved C-terminal motif in human TTP that directly binds a central domain of CNOT1, a core subunit of the CCR4-NOT complex [25].

Regulatory relationships of ZFP36

• The most widely characterized TTP-regulated gene is the AU-rich tumor necrosis factor alpha (TNF-alpha) gene [21].

Other interactions of ZFP36

• The data presented here suggest a tentative association between ZFP36 and RA [1].
• Expression of TTP and tumor necrosis factor-a (TNF-a) genes was measured by TaqMan real-time semiquantification PCR [5].
• TTP gene expression had a tendency to be inversely correlated with serum CRP, measured immediately before surgery [5].
• UV cross-linking and immunoprecipitation experiments showed that TTP expressed in HEK293 cells could associate with the PAI-2 ARE in vitro [26].
• Using pharmacologic inhibitors of the mitogen-activated protein kinase pathways, we show that the induction of TTP by LPS activation is mediated through changes in transcription, mRNA stability, and translation [27].

Analytical, diagnostic and therapeutic context of ZFP36

• Immunoblotting and immunocytochemistry indicated that endogenous and transfected hTTP localized to the cytoplasm [28].
• An immunoprecipitation reverse transcription-polymerase chain reaction technique, immunoblotting, immunocytochemistry, and sucrose density fractionation were used to identify and localize hTTP [28].
• Results from size exclusion chromatography are consistent with the predominant form of active TTP being a tetramer [4].
• Confocal microscopy showed a similar cytosolic localization of TTP among the various proteins [29].
• We investigated the phosphorylation sites in human TTP from transfected HEK-293 cells by MS and site-directed mutagenesis [29].

References