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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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Higher-power view of the radial head histology for the same littermate wild-type (a) and tristetraprolin knockout (b) mice as those shown in Fig. 2, with the radial head at the bottom of each panel. Abbreviations are as in the legend to Fig. 1. Modified from [11].
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Figure 3: Higher-power view of the radial head histology for the same littermate wild-type (a) and tristetraprolin knockout (b) mice as those shown in Fig. 2, with the radial head at the bottom of each panel. Abbreviations are as in the legend to Fig. 1. Modified from [11].

Mentions: In a larger joint, in this case the 'wrist' of the mice, the changes were more marked (Figs 2 and 3). The ordinarily delicate synovium had been transformed into an exuberant pannus, which seemed to be eroding the articular cartilage as well as underlying bone. The smaller bones of the metacarpals were often destroyed, and loss of digits was not uncommon. As in the smaller joints described above, there was marked proliferation of marrow granulocytes, essentially all of which were Gr-1+, again with internal erosion of both trabecular and cortical bone.


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)

Higher-power view of the radial head histology for the same littermate wild-type (a) and tristetraprolin knockout (b) mice as those shown in Fig. 2, with the radial head at the bottom of each panel. Abbreviations are as in the legend to Fig. 1. Modified from [11].
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Higher-power view of the radial head histology for the same littermate wild-type (a) and tristetraprolin knockout (b) mice as those shown in Fig. 2, with the radial head at the bottom of each panel. Abbreviations are as in the legend to Fig. 1. Modified from [11].
Mentions: In a larger joint, in this case the 'wrist' of the mice, the changes were more marked (Figs 2 and 3). The ordinarily delicate synovium had been transformed into an exuberant pannus, which seemed to be eroding the articular cartilage as well as underlying bone. The smaller bones of the metacarpals were often destroyed, and loss of digits was not uncommon. As in the smaller joints described above, there was marked proliferation of marrow granulocytes, essentially all of which were Gr-1+, again with internal erosion of both trabecular and cortical bone.

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