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      A Knock-In Tristetraprolin (TTP) Zinc Finger Point Mutation in Mice: Comparison with Complete TTP Deficiency

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          ABSTRACT

          Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that can bind to AU-rich element-containing mRNAs and promote their decay. TTP knockout mice develop a severe inflammatory syndrome, largely due to excess tumor necrosis factor (TNF), whose mRNA is a direct target of TTP binding and destabilization. TTP's RNA binding activity and its ability to promote mRNA decay are lost when one of the zinc-coordinating residues of either zinc finger is mutated. To address several long-standing questions about TTP activity in intact animals, we developed a knock-in mouse with a cysteine-to-arginine mutation within the first zinc finger. Homozygous knock-in mice developed a severe inflammatory syndrome that was essentially identical to that of complete TTP deficiency, suggesting that TTP's critical anti-inflammatory role in mammalian physiology is secondary to its ability to bind RNA. In addition, there was no evidence for a “dominant-negative” effect of the mutant allele in heterozygotes, as suggested by previous experiments. Finally, mRNA decay experiments in mutant macrophages demonstrated that TTP can regulate the stability of its own mRNA, albeit to a minor extent. These studies suggest that RNA binding is an essential first step in the physiological activities of members of this protein family.

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          Author and article information

          Journal
          Mol Cell Biol
          Mol. Cell. Biol
          mcb
          mcb
          MCB
          Molecular and Cellular Biology
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0270-7306
          1098-5549
          4 December 2017
          29 January 2018
          15 February 2018
          : 38
          : 4
          : e00488-17
          Affiliations
          [a ]Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
          [b ]Department of Orthopedics, Washington University School of Medicine, St. Louis, Missouri, USA
          [c ]Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA
          Author notes
          Address correspondence to Perry J. Blackshear, black009@ 123456niehs.nih.gov .
          [*]

          Present address: Lianqun Qiu, Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

          Citation Lai WS, Stumpo DJ, Qiu L, Faccio R, Blackshear PJ. 2018. A knock-in tristetraprolin (TTP) zinc finger point mutation in mice: comparison with complete TTP deficiency. Mol Cell Biol 38:e00488-17. https://doi.org/10.1128/MCB.00488-17.

          Article
          PMC5789023 PMC5789023 5789023 00488-17
          10.1128/MCB.00488-17
          5789023
          29203639
          0ae7c542-f652-4f27-bc22-3355c1d2afa4
          Copyright © 2018 American Society for Microbiology.

          All Rights Reserved.

          History
          : 13 September 2017
          : 2 October 2017
          : 25 November 2017
          Page count
          Figures: 9, Tables: 2, Equations: 0, References: 63, Pages: 21, Words: 13843
          Funding
          Funded by: National Institutes of Health (NIH);
          Award ID: Intramural Research Program of the NIEHS NIH
          Award ID: R01 AR053628
          Award ID: R01 AR066551
          Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient :
          Funded by: Shriners Hospital;
          Award ID: 85100
          Award Recipient :
          Categories
          Research Article
          Custom metadata
          February 2018

          zinc finger proteins,AU-rich elements,RNA binding proteins,inflammation,mRNA decay

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