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Tristetraprolin Regulates CXCL1 (KC) mRNA Stability¹

Shyamasree Datta^2,*, Roopa Biswas^2,, Michael Novotny^*, Paul G. Pavicic, Jr.^*, Tomasz Herjan^*, Palash Mandal^* and Thomas A. Hamilton^3,*

^* Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and Graduate School of Nursing, Uniformed Services University, Bethesda, MD 20814

mRNAs encoding proinflammatory chemokines are regulated posttranscriptionally via adenine-uridine-rich sequences (AREs) located in the 3' untranslated region of the message, which are recognized by sequence-specific RNA-binding proteins. One ARE binding protein, tristetraprolin (TTP), has been implicated in regulating the stability of several ARE-containing mRNAs, including those encoding TNF- and GM-CSF. In the present report we examined the role of TTP in regulating the decay of the mouse chemokine KC (CXCL1) mRNA. Using tetR-regulated control of transcription in TTP-deficient HEK293 cells, KC mRNA half-life was markedly decreased in the presence of TTP. Deletion and site-specific mutagenesis were used to identify multiple AUUUA sequence determinants responsible for TTP sensitivity. Although a number of studies suggest that the destabilizing activity of TTP is subject to modulation in response to ligands of Toll/IL-1 family receptors, decay mediated by TTP in 293 cells was not sensitive to stimulation with IL-1. Using primary macrophages from wild-type and TTP-deficient mice, KC mRNA instability was found to be highly dependent on TTP. Furthermore, LPS-mediated stabilization of KC mRNA is blocked by inhibition of the p38 MAPK in macrophages from wild-type but not TTP-deficient mice. These findings demonstrate that TTP is the predominant regulator of KC mRNA decay in mononuclear phagocytes acting via multiple 3'-untranslated region-localized AREs. Nevertheless, KC mRNA remains highly unstable in cells that do not express TTP, suggesting that additional determinants of instability and stimulus sensitivity may operate in cell populations where TTP is not expressed.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grants CA39621 and AI50739.

² S.D. and R.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Thomas A. Hamilton, Cleveland Clinic Foundation, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: hamiltt{at}ccf.org

⁴ Abbreviations used in this paper: TIR, Toll/IL-1 receptor; Act D, actinomycin D; ARE, adenine-uridine-rich element; CLU, cluster only; Dox, doxycycline; FL, full-length KC 3'-UTR; HA, hemagglutinin; M-MLV, Moloney murine leukemia virus; TTP, tristetraprolin; UTR, untranslated region.

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