Alternative titles; symbols
HGNC Approved Gene Symbol: ZFP36
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:39,406,847-39,409,407 (from NCBI)
The mouse tristetraprolin protein (TTP) is a basic proline-rich protein of molecular mass 33,600 Da that contains 3 PPPP repeats (Lai et al., 1990). Its mRNA level increases dramatically after stimulation with various mitogens. Also called ZFP36, Nup475 (DuBois et al., 1990), and TISII or TIS11 (Varnum et al., 1991), it has been localized to the cell nucleus and is thought to contain an unusual zinc finger structure (DuBois et al., 1990). Taylor et al. (1991) reported the sequence of human TTP, which is 87% identical to the mouse protein; the putative zinc finger structure is conserved among human, mouse and rat.
AU-rich elements (AREs) in the 3-prime untranslated regions (UTRs) of unstable mRNAs dictate their degradation. Using an RNA interference-based screen in Drosophila S2 cells, Jing et al. (2005) found that Dicer-1 (606241), Argonaute-1 (AGO1, or EIF2C1; 606228), and Ago2 (EIF2C2; 606229), components involved in microRNA (miRNA) processing and function, were required for rapid decay of mRNA containing AREs of tumor necrosis factor-alpha (TNF; 191160). The requirement for Dicer in the instability of ARE-containing mRNA (ARE-RNA) was confirmed in HeLa cells.
TTP destabilizes TNF-alpha mRNA after binding directly to the ARE of the 3-prime UTR of the TNA-alpha mRNA. Lai et al. (2000) showed that C-terminal truncated forms of TTP, as well as a 77-amino acid fragment that contains both zinc fingers, could bind to the TNF-alpha ARE in cell-free crosslinking and gel shift assays. In addition, the truncated forms of TTP could stimulate the deadenylation and/or breakdown of TNF-alpha mRNA in intact cells.
Jing et al. (2005) showed that miR16 (MIRN16-1; 609704), a human miRNA containing an UAAAUAUU sequence that is complementary to the ARE sequence, was required for ARE-RNA turnover. The role of miR16 in ARE-RNA decay was sequence-specific and required the ARE-binding protein TTP. TTP did not directly bind miR16, but interacted through association with Ago/EIF2C family members to complex with miR16 and assist in the targeting of ARE. Jing et al. (2005) concluded that miRNA targeting of ARE appears to be an essential step in ARE-mediated mRNA degradation.
Belloc and Mendez (2008) reported genomewide functional screening to identify previously unknown mRNAs cytoplasmically polyadenylated at meiotic phase transitions. A significant fraction of transcripts containing, in addition to cytoplasmic polyadenylation elements (CPEs), ARE sequences were identified. Among these is the mRNA encoding C3H-4, whose human homolog is ZFP36, an ARE-binding protein that Belloc and Mendez (2008) found to accumulate in meiosis 1 and the ablation of which induced meiotic arrest. Belloc and Mendez (2008) concluded that C3H-4 recruits the CCR4 (604836) deadenylase complex to ARE-containing mRNAs and that this, in turn, causes shortening of poly(A) tails. They also showed that the opposing activities of the CPEs and the AREs define the precise activation times of the mRNAs encoding the anaphase-promoting complex inhibitors Emi1 (606013) and Emi2 (609110) during distinct phases of the meiotic cycle. Belloc and Mendez (2008) concluded that an 'early' wave of cytoplasmic polyadenylation activates a negative feedback loop by activating the synthesis of C3H-4, which in turn would recruit the deadenylase complex to mRNAs containing both CPEs and AREs. This negative feedback loop is required to exit from metaphase into interkinesis and for meiotic progression.
O'Neil et al. (2017) generated a knockin mouse strain (Zfp36aa) in which ser52 and ser178 of the endogenous Zfp36 protein were replaced with nonphosphorylatable alanine residues. This strategy resulted in a constitutive, dominant mRNA-destabilizing protein (TTPaa) that could not be inactivated by phosphorylation via the MAPK p38 (MAPK14; 600289) pathway. Microarray analysis identified differential expression of certain Zfp36 targets in Zfp36aa homozygous macrophages; while the expression level of Il6 (147620) was not significantly different from that seen in wildtype macrophages, the expression level of Il12p40 (161561) was invariably higher. Prolonged MAPK p38 activation in macrophages lacking the MAPK phosphatase dual-specificity phosphatase-1 (DUSP1; 600714) promoted the overexpression of several inflammatory mediators that are regulated by the DUSP1-TTP axis. Overexpression of genes caused by disruption of the Dusp1 gene was prevented by the Zfp36aa genotype in Dusp1-Zfp36aa/aa macrophages since Zfp36 could not be phosphorylated and inactivated. Monitoring of gene expression at the levels of steady-state mRNA, primary transcripts, mRNA stability, and protein secretion in Zfp36aa/aa and Zfp36 +/+ macrophages revealed that the targeted mutation of Zfp36 paradoxically increased the expression of the Il6 and Il12b genes at the transcription levels. Il10 (124092), a well-characterized target of Zfp36 that negatively regulates the expression of Il12p40 and Il6, was underexpressed in Zfp36aa/aa macrophages. Further expression studies showed that the disruption of Il10 contributed to the anomalous expression of Il6 and Il12p40 in Zfp36aa/aa macrophages. However, the effects of targeted mutation of Zfp36 were not recapitulated in vivo, and Zfp36aa/aa mutant mice were uniformly antiinflammatory despite decreased expression of Il10.
Sullivan et al. (2018) found that the treatment of cells and xenografts with hyaluronidase (HAase), an enzyme that cleaves the extracellular matrix component hyaluronan, triggers a robust increase in glycolysis by destabilizing TXNIP (606599). Investigation of upstream events related to TXNIP reduction following HAase treatment found that ZFP36 expression is rapidly induced by HAase, and further analysis determined that ZFP36 promotes degradation of TXNIP mRNA in response to matrix digestion with HAase. Assessment of the phosphorylation of receptor tyrosine kinases (RTKs) further revealed that HAase treatment stimulates RTK activation, thereby subsequently inducing ZFP36 expression to deplete TXNIP, which eventually results in the increase of glycolysis in response to hyaluronan digestion.
By study of panels of rodent/human hybrid cell lines, Taylor et al. (1991) mapped the human TTP gene to chromosome 19. The mouse gene was localized to chromosome 7, using an interspecific cross. The linkage data suggested that it lies approximately 6 cM from the proximal end of mouse chromosome 7 in a region homologous with 19q13.1 in the human. This localization was confirmed by in situ hybridization of the human cDNA probe to metaphase chromosome spreads. Hoovers et al. (1992) also assigned zinc finger protein genes to both 19p and 19qter and commented on the fact that a number of finger protein genes occur in linked clusters. This mapping was part of an identification and partial characterization of 101 potential human zinc finger protein genes which were isolated with an oligonucleotide specific for the sequence that frequently links contiguous zinc fingers. See Huebner et al. (1993) for the assignment of other zinc finger protein genes to 19q.
TNF-alpha is a major mediator of both acute and chronic inflammatory responses in many diseases. In addition to its well-known role in acute septic shock, it has been implicated in the pathogenesis of chronic processes such as autoimmunity, graft-versus-host disease (GVHD; see 614395), rheumatoid arthritis, Crohn disease, and the cachexia accompanying cancer and AIDS. Treatments such as neutralizing antibodies to TNF-alpha and chimeric soluble TNF-alpha receptors have demonstrated efficacy against some of these conditions in clinical trials (Lorenz et al., 1996; Abraham et al., 1997). Carballo et al. (1998) developed mice deficient in Ttp. Although the Ttp-deficient mice appeared normal at birth, they soon developed a complex syndrome of inflammatory arthritis, dermatitis, cachexia, autoimmunity, and myeloid hyperplasia. Essentially all aspects of this syndrome could be prevented by repeated injections of antibodies to TNF-alpha. Macrophages derived from the liver of Ttp-deficient fetuses, or from bone marrow precursors or resident peritoneal macrophages from adult mice, exhibited increased production of TNF-alpha, as well as increased amounts of TNF-alpha mRNA, after stimulation with lipopolysaccharide (LPS). Carballo et al. (1998) demonstrated direct Ttp binding to the AU-rich element of the TNF-alpha mRNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-alpha production, including TNF-alpha itself. These findings identified TTP as a component of a negative feedback loop that interferes with TNF-alpha production by destabilizing its mRNA. This pathway represents a potential target for anti-TNF-alpha therapies.
As indicated, deficiency of TTP results in a complex inflammatory syndrome in mice. Most aspects of the syndrome are secondary to excess circulating tumor necrosis factor, a consequence of increased stability of TNF-alpha mRNA in Ttp-deficient macrophages. TTP can bind directly to the AU-rich element in TNF-alpha mRNA, increasing its lability. Carballo et al. (2000) showed that Ttp deficiency also results in increased cellular production of granulocyte-macrophage colony-stimulating factor (CFS2; 138960) and increased stability of its mRNA, apparently secondary to decreased deadenylation. Similar findings were observed in mice also lacking both types of TNF-alpha receptors, excluding excess TNF-alpha production as a cause of the increased CSF2 mRNA levels and stability. TTP appears to be a physiologic regulator of CSF2 mRNA deadenylation and stability.
After identifying AREs within the 3-prime UTRs of mouse and human IL12A (161560), IL12B (161561), and IL23A (605580), Molle et al. (2013) used bone marrow-derived dendritic cells from Ttp -/- mice to assess the effects of Ttp on Il23 production. Production of Il12b in response to LPS stimulation was normal, and that of the IL12 heterodimer was modestly increased. In contrast, production of Il23a and the Il23 heterodimer, as well as stability of Il23a mRNA, were greatly enhanced. Ttp -/- mice developed an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. Il23a was found within skin lesions associated with Il17a (603149) and Il22 (605330) production by infiltrating gamma-delta T cells and Cd4 T cells. Molle et al. (2013) concluded that the clinical and immunologic manifestations of Ttp deficiency are completely dependent on the Il23-Il17a axis and that control of Il23 mRNA stability is critical to avoid severe inflammation.
Abraham, E., Glauser, M. P., Butler, T., Garbino, J., Gelmont, D., Laterre, P. F., Kudsk, K., Bruining, H. A., Otto, C., Tobin, E., Zwingelstein, C., Lesslauer, W., Leighton, A. p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. JAMA 277: 1531 only, 1997. [PubMed: 9153367]
Belloc, E., Mendez, R. A deadenylation negative feedback mechanism governs meiotic metaphase arrest. Nature 452: 1017-1021, 2008. [PubMed: 18385675] [Full Text: https://doi.org/10.1038/nature06809]
Carballo, E., Lai, W. S., Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 281: 1001-1005, 1998. [PubMed: 9703499] [Full Text: https://doi.org/10.1126/science.281.5379.1001]
Carballo, E., Lai, W. S., Blackshear, P. J. Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood 95: 1891-1899, 2000. [PubMed: 10706852]
DuBois, R. N., McLane, M. W., Ryder, K., Lau, L. F., Nathans, D. A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence. J. Biol. Chem. 265: 19185-19191, 1990. [PubMed: 1699942]
Hoovers, J. M. N., Mannens, M., John, R., Bliek, J., van Heyningen, V., Porteous, D. J., Leschot, N. J., Westerveld, A., Little, P. F. R. High-resolution localization of 69 potential human zinc finger protein genes: a number are clustered. Genomics 12: 254-263, 1992. [PubMed: 1740334] [Full Text: https://doi.org/10.1016/0888-7543(92)90372-y]
Huebner, K., Druck, T., LaForgia, S., Lasota, J., Croce, C. M., Lanfrancone, L., Donti, E., Pengue, G., La Mantia, G., Pelicci, P.-G., Lania, L. Chromosomal localization of four human zinc finger cDNAs. Hum. Genet. 91: 217-222, 1993. [PubMed: 8478004] [Full Text: https://doi.org/10.1007/BF00218259]
Jing, Q., Huang, S., Guth, S., Zarubin, T., Motoyama, A., Chen, J., Di Padova, F., Lin, S.-C., Gram, H., Han, J. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120: 623-634, 2005. [PubMed: 15766526] [Full Text: https://doi.org/10.1016/j.cell.2004.12.038]
Lai, W. S., Carballo, E., Thorn, J. M., Kennington, E. A., Blackshear, P. J. 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, 2000. [PubMed: 10751406] [Full Text: https://doi.org/10.1074/jbc.M001696200]
Lai, W. S., Stumpo, D. J., Blackshear, P. J. Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein. J. Biol. Chem. 265: 16556-16563, 1990. [PubMed: 2204625]
Lorenz, H. M., Antoni, C., Valerius, T., Repp, R., Grunke, M., Schwerdtner, N., Nusslein, H., Woody, J., Kalden, J. R., Manger, B. In vivo blockade of TNF-alpha by intravenous infusion of a chimeric monoclonal TNF-alpha antibody in patients with rheumatoid arthritis. Short term cellular and molecular effects. J. Immun. 156: 1646-1653, 1996. [PubMed: 8568271]
Molle, C., Zhang, T., de Lendonck, L. Y., Gueydan, C., Andrianne, M., Sherer, F., Van Simaeys, G., Blackshear, P. J., Leo, O., Goriely, S. Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease. J. Exp. Med. 210: 1675-1684, 2013. [PubMed: 23940256] [Full Text: https://doi.org/10.1084/jem.20120707]
O'Neil, J. D., Ross, E. A., Ridley, M. L., Ding, Q., Tang, T., Rosner, D. R., Crowley, T., Malhi, D., Dean, J. L., Smallie, T., Buckley, C. D., Clark, A. R. Gain-of-function mutation of tristetraprolin impairs negative feedback control of macrophages in vitro yet has overwhelmingly anti-inflammatory consequences in vivo. Molec. Cell. Biol. 37: e00536-16, 2017. Note: Electronic Article. [PubMed: 28265004] [Full Text: https://doi.org/10.1128/MCB.00536-16]
Sullivan, W. J., Mullen, P. J., Schmid, E. W., Flores, A., Momcilovic, M., Sharpley, M. S., Jelinek, D., Whiteley, A. E., Maxwell, M. B., Wilde, B. R., Banerjee, U., Coller, H. A., Shackelford, D. B., Braas, D., Ayer, D. E., de Aguiar Vallim, T. Q., Lowry, W. E., Christofk, H. R. Extracellular matrix remodeling regulates glucose metabolism through TXNIP destabilization. Cell 175: 117-132, 2018. [PubMed: 30197082] [Full Text: https://doi.org/10.1016/j.cell.2018.08.017]
Taylor, G. A., Lai, W. S., Oakey, R. J., Seldin, M. F., Shows, T. B., Eddy, R. L., Jr., Blackshear, P. J. The human TTP protein: sequence, alignment with related proteins, and chromosomal localization of the mouse and human genes. Nucleic Acids Res. 19: 3454 only, 1991. [PubMed: 2062660] [Full Text: https://doi.org/10.1093/nar/19.12.3454]
Varnum, B. C., Ma, Q., Chi, T., Fletcher, B., Herschman, H. R. The TIS11 primary response gene is a member of a gene family that encodes proteins with a highly conserved sequence containing an unusual cys-his repeat. Molec. Cell. Biol. 11: 1754-1758, 1991. [PubMed: 1996120] [Full Text: https://doi.org/10.1128/mcb.11.3.1754-1758.1991]