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Tristetraprolin, a Negative Regulator of mRNA Stability, Is Increased in Old B Cells and Is Involved in the Degradation of E47 mRNA¹

Daniela Frasca^*,, Ana Marie Landin^*, Juan P. Alvarez^*, Perry J. Blackshear, Richard L. Riley^* and Bonnie B. Blomberg^2,*

^* Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101; Graduate School of Cell Biology and Development, University of Rome La Sapienza, Rome, Italy; and National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709

We have previously shown that the E2A-encoded transcription factor E47, which regulates class switch in splenic B cells, is down-regulated in old B cells, due to increased E47 mRNA decay. At least part of the decreased stability of E47 mRNA seen in aged B cells is mediated by proteins. We have herein looked at the specific proteins responsible for the degradation of the E47 mRNA and found that tristetraprolin (TTP), a physiological regulator of mRNA expression and stability, is involved in the degradation of the E47 mRNA. Although many studies have characterized TTP expression and function in macrophages, monocytes, mast cells, and T cells, little is known about the expression and function of TTP in primary B cells. We show herein that TTP mRNA and protein expression are induced by LPS in B cells from young and old mice, the levels of TTP in old B cells always being higher than those in young B cells. Although TTP mRNA is degraded at a significantly higher rate in old B cells, TTP mRNA expression is higher in old than in young, likely due to its increased transcription. Like in macrophages, TTP protein expression and function in B cells are dependent upon p38 MAPK. We found that there is less phospho-TTP (inactive form), as well as phospho-p38, in old than in young splenic-activated B cells. This is the first report showing that TTP is involved in the degradation of the E47 mRNA and is up-regulated in old B cells.

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 National Institutes of Health AG-17618 and AG-23717 (to B.B.B.) and by National Institute of Health AG-025256 and AI-064591 (to R.L.R.).

² Address correspondence and reprint requests to Dr. Bonnie B. Blomberg, Department of Microbiology and Immunology, University of Miami Miller School of Medicine, P.O. Box 016960 (R-138), Miami, FL 33101. E-mail address: bblomber{at}med.miami.edu

³ Abbreviations used in this paper: CSR, class switch recombination; AID, activation-induced cytidine deaminase; ARE, AU-rich element; UTR, untranslated region; BP, binding protein; TTP, tristetraprolin; FO, follicular; MZ, marginal zone; rt, room temperature; RT, reverse transcriptase; siRNA, small-interfering RNA; IP, immunoprecipitation; MK, MAPK-activated protein kinase; WB, Western blot; miRNA, microRNA.

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