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The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis.

Carrick DM, Lai WS, Blackshear PJ - Arthritis Res. Ther. (2004)

Bottom Line: The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine.Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex.The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Office of Clinical Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

ABSTRACT
Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with highly conserved sequences and spacing. Although initially discovered as a gene that could be induced rapidly and transiently by the stimulation of fibroblasts with growth factors and mitogens, it is now known that TTP can bind to AU-rich elements in mRNA, leading to the removal of the poly(A) tail from that mRNA and increased rates of mRNA turnover. This activity was discovered after TTP-deficient mice were created and found to have a systemic inflammatory syndrome with severe polyarticular arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia. The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine. The myeloid hyperplasia might be due in part to increased stability of granulocyte-macrophage colony-stimulating factor (GM-CSF). This review highlights briefly the characteristics of the TTP-deficiency syndrome in mice and its possible genetic modifiers, as well as recent data on the characteristics of the TTP-binding site in the TNF-alpha and GM-CSF mRNAs. Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex. We review the current knowledge of TTP sequence variants in humans and discuss the possible contributions of the TTP-related proteins in mouse physiology and in human monocytes. The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

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Mammalian tumour necrosis factor-α (TNF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) AU-rich elements (AREs). (a) The central ARE region of the TNF mRNA 3' untranslated region from all mammalian species for which this region of the mRNA has been deposited in GenBank. In most cases these were derived from EST sequences; note that the horse sequence has not been completed at the 3' end. The overlines indicate the nine-base tristetraprolin (TTP)-binding site 5'-UUAUUUAUU-3'. Sequences from the various mammals are divided into groups based on the pattern of these nonamers, with the top group of 10 mammals being the most common group. (b) A similar approach was used to align the central ARE from the GM-CSF transcript, after alignment using the program ClustalW. The asterisks below the alignment represent base identity at that position; note that gaps were used to optimize the alignment. The overlines again represent the nonamer TTP-binding site. These data are modified from [37].
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Figure 5: Mammalian tumour necrosis factor-α (TNF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) AU-rich elements (AREs). (a) The central ARE region of the TNF mRNA 3' untranslated region from all mammalian species for which this region of the mRNA has been deposited in GenBank. In most cases these were derived from EST sequences; note that the horse sequence has not been completed at the 3' end. The overlines indicate the nine-base tristetraprolin (TTP)-binding site 5'-UUAUUUAUU-3'. Sequences from the various mammals are divided into groups based on the pattern of these nonamers, with the top group of 10 mammals being the most common group. (b) A similar approach was used to align the central ARE from the GM-CSF transcript, after alignment using the program ClustalW. The asterisks below the alignment represent base identity at that position; note that gaps were used to optimize the alignment. The overlines again represent the nonamer TTP-binding site. These data are modified from [37].

Mentions: Given that these studies have all agreed that the central optimal binding motif is 5'-UUAUUUAUU-3', it is of interest to compare this sequence with the naturally occurring physiological targets of TTP found in the TNF-α and GM-CSF mRNAs. Figure 5 shows the central ARE sequences from all known mammalian orthologs of the TNF-α and GM-CSF mRNAs [37]. It should be noted that the extreme conservation of these motifs falls apart in both the 5' and 3' direction in both TNF-α and GM-CSF mRNAs. By far the most popular mammalian pattern in the TNF-α mRNA is exemplified by the human sequence and those of nine other mammals, in which there are five overlapping versions of the nonamer-binding site. Within the five overlapping nonamers are several non-overlapping patterns. It will be of great interest to determine how many intact TZF peptide and intact TTP protein molecules can bind to this sequence, because it might be expected that the overlapping nonamers might prevent binding to some of the neighboring nonamers by steric hindrance. It is also of interest that several other mammals have different patterns and total numbers of these nonamers (Fig. 5a); again, it will be of interest to determine whether there are species differences in the number of TTP molecules that can occupy these domains, perhaps resulting in species differences in TTP effects on mRNA turnover rates.


The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis.

Carrick DM, Lai WS, Blackshear PJ - Arthritis Res. Ther. (2004)

Mammalian tumour necrosis factor-α (TNF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) AU-rich elements (AREs). (a) The central ARE region of the TNF mRNA 3' untranslated region from all mammalian species for which this region of the mRNA has been deposited in GenBank. In most cases these were derived from EST sequences; note that the horse sequence has not been completed at the 3' end. The overlines indicate the nine-base tristetraprolin (TTP)-binding site 5'-UUAUUUAUU-3'. Sequences from the various mammals are divided into groups based on the pattern of these nonamers, with the top group of 10 mammals being the most common group. (b) A similar approach was used to align the central ARE from the GM-CSF transcript, after alignment using the program ClustalW. The asterisks below the alignment represent base identity at that position; note that gaps were used to optimize the alignment. The overlines again represent the nonamer TTP-binding site. These data are modified from [37].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064869&req=5

Figure 5: Mammalian tumour necrosis factor-α (TNF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) AU-rich elements (AREs). (a) The central ARE region of the TNF mRNA 3' untranslated region from all mammalian species for which this region of the mRNA has been deposited in GenBank. In most cases these were derived from EST sequences; note that the horse sequence has not been completed at the 3' end. The overlines indicate the nine-base tristetraprolin (TTP)-binding site 5'-UUAUUUAUU-3'. Sequences from the various mammals are divided into groups based on the pattern of these nonamers, with the top group of 10 mammals being the most common group. (b) A similar approach was used to align the central ARE from the GM-CSF transcript, after alignment using the program ClustalW. The asterisks below the alignment represent base identity at that position; note that gaps were used to optimize the alignment. The overlines again represent the nonamer TTP-binding site. These data are modified from [37].
Mentions: Given that these studies have all agreed that the central optimal binding motif is 5'-UUAUUUAUU-3', it is of interest to compare this sequence with the naturally occurring physiological targets of TTP found in the TNF-α and GM-CSF mRNAs. Figure 5 shows the central ARE sequences from all known mammalian orthologs of the TNF-α and GM-CSF mRNAs [37]. It should be noted that the extreme conservation of these motifs falls apart in both the 5' and 3' direction in both TNF-α and GM-CSF mRNAs. By far the most popular mammalian pattern in the TNF-α mRNA is exemplified by the human sequence and those of nine other mammals, in which there are five overlapping versions of the nonamer-binding site. Within the five overlapping nonamers are several non-overlapping patterns. It will be of great interest to determine how many intact TZF peptide and intact TTP protein molecules can bind to this sequence, because it might be expected that the overlapping nonamers might prevent binding to some of the neighboring nonamers by steric hindrance. It is also of interest that several other mammals have different patterns and total numbers of these nonamers (Fig. 5a); again, it will be of interest to determine whether there are species differences in the number of TTP molecules that can occupy these domains, perhaps resulting in species differences in TTP effects on mRNA turnover rates.

Bottom Line: The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine.Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex.The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Office of Clinical Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

ABSTRACT
Tristetraprolin (TTP) is the best-studied member of a small family of three proteins in humans that is characterized by a tandem CCCH zinc finger (TZF) domain with highly conserved sequences and spacing. Although initially discovered as a gene that could be induced rapidly and transiently by the stimulation of fibroblasts with growth factors and mitogens, it is now known that TTP can bind to AU-rich elements in mRNA, leading to the removal of the poly(A) tail from that mRNA and increased rates of mRNA turnover. This activity was discovered after TTP-deficient mice were created and found to have a systemic inflammatory syndrome with severe polyarticular arthritis and autoimmunity, as well as medullary and extramedullary myeloid hyperplasia. The syndrome seemed to be due predominantly to excess circulating tumor necrosis factor-alpha (TNF-alpha), resulting from the increased stability of the TNF-alpha mRNA and subsequent higher rates of secretion of the cytokine. The myeloid hyperplasia might be due in part to increased stability of granulocyte-macrophage colony-stimulating factor (GM-CSF). This review highlights briefly the characteristics of the TTP-deficiency syndrome in mice and its possible genetic modifiers, as well as recent data on the characteristics of the TTP-binding site in the TNF-alpha and GM-CSF mRNAs. Recent structural data on the characteristics of the complex between RNA and one of the TTP-related proteins are reviewed, and used to model the TTP-RNA binding complex. We review the current knowledge of TTP sequence variants in humans and discuss the possible contributions of the TTP-related proteins in mouse physiology and in human monocytes. The TTP pathway of TNF-alpha and GM-CSF mRNA degradation is a possible novel target for anti-TNF-alpha therapies for rheumatoid arthritis, and also for other conditions proven to respond to anti-TNF-alpha therapy.

Show MeSH
Related in: MedlinePlus